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Vibration training intervention to maintain cartilage thickness and serum concentrations of cartilage oligometric matrix protein (COMP) during immobilization
Abstract
To test the hypotheses that 1) 14-days of immobilization of young healthy subjects using a 6 degrees -"head-down-tilt-bed-rest"-model (6 degrees -HDT) would reduce cartilage thickness in the knee and serum Cartilage oligometric matrix protein (COMP) concentration and 2) isolated whole body vibration training would counteract the bed rest effects.
The study was performed and designed in compliance with the Declaration of Helsinki and is registered as trial DRKS00000140 in the German Clinical Trial Register (register.germanctr.de). Eight male healthy subjects (78.0+/-9.5kg; 179+/-0.96cm, 26+/-5 years) performed 14 days of 6 degrees -HDT. The study was designed as a cross-over-design with two study phases: a training and a control intervention. During the training intervention, subjects underwent 2x5-min whole body vibration training/day (Frequency: 20Hz; amplitude: 2-4mm). Magnetic resonance (MR) images (slice thickness: 2mm; in-plane resolution: 0.35x0.35mm; pixels: 448x512) were taken before and after the 6 degrees -HDT periods. Average cartilage thicknesses were calculated for the load bearing regions on the medial and lateral articulating surfaces in the femur and tibia.
While the control intervention resulted in an overall loss in average cartilage thickness of -8% (pre: 3.08mm+/-0.6mm post: 2.82mm+/-0.6mm) in the weight-bearing regions of the tibia, average cartilage thickness increased by 21.9% (pre: 2.66mm+/-0.45mm post: 3.24mm+/-0.63mm) with the vibration intervention. No significant differences were found in the weight-bearing regions of the femur. During both interventions, reduced serum COMP concentrations were observed (control intervention: -13.6+/-8.4%; vibration intervention: -9.9+/-3.3%).
The results of this study suggest that articular cartilage thickness is sensitive to unloading and that vibration training may be a potent countermeasure against these effects. The sensitivity of cartilage to physical training is of high relevance for training methods in space flight, elite and sport and rehabilitation after illness or injury.
... Die Arbeitsgruppe zog hieraus den Schluss, dass eine RA-Erkrankung die COMP-Kinetik in Reaktion auf Training nicht signifikant verändere (Law et al., 2015). A. M. Liphardt et al. zeigten, dass auch unzureichende körperliche Aktivität Auswirkungen auf COMP hat(Liphardt et al., 2009, Liphardt et al., 2018. Neben diesem Immobilisationseffekt konnten A. M. Liphardt und Kollegen später auch nachweisen, dass sich das Absinken des COMP-Spiegels als Immobilisationsfolge durch einfache Interventionen wie aufrechtes Stehen oder eine Vibrationsintervention nicht verhindern lässt(Liphardt et al., 2020a, Liphardt et al., 2009). ...
... A. M. Liphardt et al. zeigten, dass auch unzureichende körperliche Aktivität Auswirkungen auf COMP hat(Liphardt et al., 2009, Liphardt et al., 2018. Neben diesem Immobilisationseffekt konnten A. M. Liphardt und Kollegen später auch nachweisen, dass sich das Absinken des COMP-Spiegels als Immobilisationsfolge durch einfache Interventionen wie aufrechtes Stehen oder eine Vibrationsintervention nicht verhindern lässt(Liphardt et al., 2020a, Liphardt et al., 2009). Bei der Untersuchung der Auswirkungen der Vibrationsintervention ergab sich darüber hinaus die Beobachtung, dass die Knorpeldicke nur in der Kontrollgruppe abnahm, während sie in der Vibrationskohorte sogar einen Anstieg verzeichnete(Liphardt et al., 2009).Mit dem Wissen über die Ruhe-und Bewegungsabhängigkeit der COMP-Level sind standardisierte Bedingungen in Studien, die COMP untersuchen wollen, selbsterklärend sinnvoll. ...
... Neben diesem Immobilisationseffekt konnten A. M. Liphardt und Kollegen später auch nachweisen, dass sich das Absinken des COMP-Spiegels als Immobilisationsfolge durch einfache Interventionen wie aufrechtes Stehen oder eine Vibrationsintervention nicht verhindern lässt(Liphardt et al., 2020a, Liphardt et al., 2009). Bei der Untersuchung der Auswirkungen der Vibrationsintervention ergab sich darüber hinaus die Beobachtung, dass die Knorpeldicke nur in der Kontrollgruppe abnahm, während sie in der Vibrationskohorte sogar einen Anstieg verzeichnete(Liphardt et al., 2009).Mit dem Wissen über die Ruhe-und Bewegungsabhängigkeit der COMP-Level sind standardisierte Bedingungen in Studien, die COMP untersuchen wollen, selbsterklärend sinnvoll. Eine gängige Empfehlung ist, dass Probanden vor der Erhebung der COMP-Ausgangswerte für einen festen Zeitraum ruhen sollten (beispielsweise 30 min), um Effekte vorheriger Bewegung auf das Serum-COMP-Level zu verringern(Niehoff et al., 2010). ...
Hintergrund und Ziele Rheumatoide Arthritis (RA) ist eine häufige und gesundheitspolitisch relevante Erkrankung (Smolen et al., 2016a). Trotz sich weiterentwickelnder Therapieoptionen ist eine Heilung bisher nicht möglich. Frühe oder der RA vorausgehende Stadien zu diagnostizieren, ist ein wichtiger Ansatz, um das Verständnis der Pathophysiologie zu verbessern und neue Therapie-möglichkeiten zu schaffen (Greenblatt et al., 2020). Eine von der European Alliance of Associations for Rheumatology (EULAR) beschriebene Gruppe mit Risiko für eine spätere RA-Erkrankung sind Menschen, die positiv für RA-assoziierte Antikörper (AK) sind (Gerlag et al., 2012). Hierzu zählen AK gegen citrullinierte Peptide (ACPAs) (Sokolove et al., 2012). Die Relevanz von ACPAs für Knochenschäden ist bekannt und eine mögliche Auswirkung auf Knorpelgewebe wird diskutiert (Kleyer et al., 2014, Renner et al., 2014). ACPA-positive Personen ohne klinische RA-Manifestation werden in dieser Arbeit als prä-RA bezeichnet. Zur Untersuchung von Knorpelstoffwechsel werden verschiedene Biomarker verwendet. Cartilage Oligomeric Matrix Protein (COMP) ist ein wichtiger Vertreter der im Serum nachweisbaren Knorpelmarker. Seine Mechanosensitivität ist bekannt (Giannoni et al., 2003). Ein möglicher prognostischer Wert für spätere Knorpelschäden wird diskutiert (Neidhart et al., 2000). Hinweise auf Unterschiede im Knorpelstoffwechsel zwischen RA und prä-RA sollen mit der Analyse der COMP-Level weiter untersucht werden. Bei bekannter Mechanosensitivität von COMP sind hierbei standardisierte Untersuchungsbedingungen essenziell und die Analyse des körperlichen Aktivitätslevels der Probanden sinnvoll (Niehoff et al., 2010). Ziel der vorliegenden Arbeit ist die Untersuchung der Unterschiede zwischen den Diagnosegruppen RA und prä-RA in Bezug auf die körperliche Aktivität und die COMP-Werte. Weiter wird die Abhängigkeit der COMP-Level von der körperlichen Aktivität, der Krankheitsaktivität und der empfundenen Bewegungseinschränkung evaluiert. Teilergebnisse der vorliegenden Arbeit wurden veröffentlicht in: Bleckwedel-Rolack L, Tascilar K, Nees V, Hühne J, Hueber A, Rech J, Schett G, Kleyer A, Liphardt A M (2021) Patients at risk for RA show the same amount of acute soluble cartilage degradation markers after physi-cal activity compared to patients with established RA. Annals of the Rheumatic Diseases, 80: 420-421 sowie beim EULAR 2021 als Poster (POS0381) präsentiert. Ein weiteres Abstract mit dem Titel „Acute response of a soluble cartilage degradation marker to a 30-minute walking exercise is similar in patients at risk of RA compared to patients with established RA“ wurde für den Deutschen Rheumatologiekongress 2021 (Abstract-Nr. 204) angenommen. Die Veröffentlichungen des Abstracts und des zugehörigen Posters (Nr. RA 44) stehen noch aus. Methoden Die untersuchte Kohorte bestand aus 28 RA und 22 prä-RA-Patienten. Die Probanden wurden zu jeweils drei Visiten geladen, bei denen sie eine 30-minütige Bewegungsintervention auf dem Laufband in selbst gewähltem Tempo durchführten. In bestimmten Abständen zur Inter-vention erfolgten Blutentnahmen. Aus dem gewonnenen Serum wurde mittels Sandwich-Enzyme-linked Immunosorbent Assay (ELISA) die Bestimmung der COMP-Level vorgenom-men. Zur Verifizierung der körperlichen Aktivität im Alltag füllten die Probanden bei den Visiten einen Fragebogen, den International Physical Activity Questionnaire (IPAQ), aus und trugen im Anschluss einen Aktivitätsmonitor für die folgenden sieben Tage. Die Krankheitsaktivität wurde mittels Disease Activity Score 28 (DAS 28) und die subjektive Bewegungseinschrän-kung im Health Assessment Questionnaire-Disability Index (HAQ-DI) erfasst. Ergebnisse und Beobachtungen Die Diagnosegruppen prä-RA und RA unterschieden sich im Untersuchungszeitraum nicht bezüglich der COMP-Level oder der -Kinetik. Während sich kein Zusammenhang zwischen COMP-Level und DAS 28 zeigte, war ein steigender HAQ-DI mit niedrigeren COMP-Werten assoziiert. RA-Patienten hatten in der Aktivitätsmonitor-Datenauswertung eine um 22,3 % hö-here mittlere körperliche Aktivitätsdauer als prä-RA-Patienten. Ein positiver Zusammenhang der körperlichen Gesamtaktivitätsdauer mit dem COMP-Level war nur für prä-RA nachweisbar. Schlussfolgerungen und Diskussion Keinen Unterschied zwischen den Diagnosegruppen bezüglich der allgemeinen COMP-Level und deren Reaktion auf die Bewegungsintervention nachweisen zu können, deutet eventuell auf einen Knorpelstoffwechsel hin, der Parallelen zum ACPA-abhängigem Knochenverlust zeigt. Hierbei ist allerdings zu berücksichtigen, dass sich die COMP-Level in prä-RA- und RA- nicht deutlich von denen in gesunden Probanden oder Osteoarthritis (OA)-Patienten aus an-deren Studien unterscheiden (Mundermann et al., 2009). Ob sich mögliche, durch ACPA-Positivität bedingte Veränderungen im Knorpelstoffwechsel wirklich auf die COMP-Reaktion nach einer Gehbelastung auswirken, sollte daher in künftigen Untersuchungen mit einer ge-sunden Vergleichsgruppe evaluiert werden. Dass lediglich Individuen mit prä-RA eine positive Korrelation von COMP und Gesamtaktivitätsdauer zeigen, lässt sich eventuell auf eine sich unterscheidende Knorpelvitalität zwischen prä-RA- und RA-Diagnosegruppen zurückführen. Bilddatenauswertungen zur Knorpeldicke der Probanden könnten diese Annahme überprüfen. Ein weiterer möglicher Untersuchungsgegenstand wäre eine möglicherweise zwischen den Gruppen verschiedene qualitative Gelenkbelastung. Dies könnte mittels einer Videoanalyse der Bewegungsabläufe während der Gehbelastung überprüft werden.
... An umbrella review reported that moderate evidence supports the role of WBV as a viable clinical intervention for managing KOA, although more studies are still warranted [15]. In a crossover investigation, Liphardt et al. [16] verified that WBV can prevent the loss of tibial articular cartilage thickness (determined by magnetic resonance image) after prolonged immobilization in healthy male individuals. Moreover, authors reported that mechanical vibration can lead to adaptations in muscle and bone [16,17]. ...
... In a crossover investigation, Liphardt et al. [16] verified that WBV can prevent the loss of tibial articular cartilage thickness (determined by magnetic resonance image) after prolonged immobilization in healthy male individuals. Moreover, authors reported that mechanical vibration can lead to adaptations in muscle and bone [16,17]. In rats, according to Musumeci et al. [18], it is possible that the mechanical stimulation in the articular cartilage could release lubricin antibodies that are capable of inhibiting caspase-3 activity, preventing chondrocyte death. ...
... In consequence, mechanical stimulation could be a possible therapeutic treatment, as in osteoporosis, and mild physical activity could also be used as a therapeutic treatment for cartilage disease such as osteoarthritis [18]. Although WBV has shown importance in improving various parameters related to the joint [16,18], it is relevant to consider some undesirable findings, such as the deleterious e↵ect of prolonged vibration from o↵-road motorcycling on the elbow joint [19]. ...
Abstract: Knee osteoarthritis (KOA) can cause functional disability. Neuromuscular function isrelevant in the development and progression of KOA. It can be evaluated by the analysis of the surfaceelectromyography (sEMG), which has an important role in the understanding of KOA. Whole-bodyvibration (WBV) is an intervention suggested to treat KOA. The objective of this work was to verifythe e↵ectiveness of WBV on the functionality of lower limbs by the electromyographic profile ofthe vastus lateralis (VL) muscles during the five-repetition chair stand test (5CST) in patients withKOA. This was a two-period crossover trial study (8-week washout). Nineteen patients with KOAwere allocated to the group submitted to WBV (WBVG), with peak-to-peak displacement of 2.5to 7.5 mm, frequency from 5 to 14 Hz, and acceleration peak from 0.12 to 2.95 g, or to the controlgroup (0 Hz) (2 days per week for 5 weeks). The 5CST and the sEMG of the VL during 5CST wereevaluated before and after the interventions. Results: Significant di↵erences in 5CST were evidentonly in WBVG (p = 0.018), showing a decrease of the execution time. The sEMG profile showed nosignificative di↵erence. Therefore, only 10 sessions of WBV with comfortable posture can bring aboutimprovement in functionality of KOA patients without alteration of the muscle excitation.Keywords: knee osteoarthritis; conservative treatment; whole-body vibration; electromyography;physical and rehabilitation medicine
... An umbrella review reported that moderate evidence supports the role of WBV as a viable clinical intervention for managing KOA, although more studies are still warranted [15]. In a crossover investigation, Liphardt et al. [16] verified that WBV can prevent the loss of tibial articular cartilage thickness (determined by magnetic resonance image) after prolonged immobilization in healthy male individuals. Moreover, authors reported that mechanical vibration can lead to adaptations in muscle and bone [16,17]. ...
... In a crossover investigation, Liphardt et al. [16] verified that WBV can prevent the loss of tibial articular cartilage thickness (determined by magnetic resonance image) after prolonged immobilization in healthy male individuals. Moreover, authors reported that mechanical vibration can lead to adaptations in muscle and bone [16,17]. In rats, according to Musumeci et al. [18], it is possible that the mechanical stimulation in the articular cartilage could release lubricin antibodies that are capable of inhibiting caspase-3 activity, preventing chondrocyte death. ...
... In consequence, mechanical stimulation could be a possible therapeutic treatment, as in osteoporosis, and mild physical activity could also be used as a therapeutic treatment for cartilage disease such as osteoarthritis [18]. Although WBV has shown importance in improving various parameters related to the joint [16,18], it is relevant to consider some undesirable findings, such as the deleterious effect of prolonged vibration from off-road motorcycling on the elbow joint [19]. ...
Knee osteoarthritis (KOA) can cause functional disability. Neuromuscular function is relevant in the development and progression of KOA. It can be evaluated by the analysis of the surface electromyography (sEMG), which has an important role in the understanding of KOA. Whole-body vibration (WBV) is an intervention suggested to treat KOA. The objective of this work was to verify the effectiveness of WBV on the functionality of lower limbs by the electromyographic profile of the vastus lateralis (VL) muscles during the five-repetition chair stand test (5CST) in patients with KOA. This was a two-period crossover trial study (8-week washout). Nineteen patients with KOA were allocated to the group submitted to WBV (WBVG), with peak-to-peak displacement of 2.5 to 7.5 mm, frequency from 5 to 14 Hz, and acceleration peak from 0.12 to 2.95 g, or to the control group (0 Hz) (2 days per week for 5 weeks). The 5CST and the sEMG of the VL during 5CST were evaluated before and after the interventions. Results: Significant differences in 5CST were evident only in WBVG (p = 0.018), showing a decrease of the execution time. The sEMG profile showed no significative difference. Therefore, only 10 sessions of WBV with comfortable posture can bring about improvement in functionality of KOA patients without alteration of the muscle excitation.
... 14,17,[20][21][22][23] Moreover, immobilization of healthy individuals using bed rest has led to a decrease in serum COMP concentration. 24 Matrix metalloproteinases (MMPs) are a multimember family of proteases that are involved in the degradation of the cartilage matrix components 25 and represent the main proteolytic enzyme group involved in remodeling the extracellular matrix and modifying cell-cell and cellmatrix interactions. 26 Previous studies have suggested that MMPs play a key role in regulating the balance of structural proteins of the articular cartilage matrix according to local mechanical demands. ...
... Previous work by our group and others suggests that immobilization can initiate cartilage degeneration 10,11,24,[37][38][39][40][41][42] leading to an increased health risk for human space flight 7 and that current countermeasure regiments may not be capable of addressing cartilage health. 24 Moreover, there is evidence from animal models to suggest that radiation exposure may enhance the deteriorating effects of immobilization on cartilage health, which needs to be further investigated in humans. ...
... Previous work by our group and others suggests that immobilization can initiate cartilage degeneration 10,11,24,[37][38][39][40][41][42] leading to an increased health risk for human space flight 7 and that current countermeasure regiments may not be capable of addressing cartilage health. 24 Moreover, there is evidence from animal models to suggest that radiation exposure may enhance the deteriorating effects of immobilization on cartilage health, which needs to be further investigated in humans. 7,43 While exercise countermeasures are currently implemented on the International Space Station (ISS) the optimal training regimen has yet to be found. ...
Biomarkers of cartilage metabolism are sensitive to changes in the biological and mechanical environment and can indicate early changes in cartilage homeostasis. The purpose of this study was to determine if a daily locomotion replacement program can serve as a countermeasure for changes in cartilage biomarker serum concentration caused by immobilization. Ten healthy male subjects (mean ± 1 standard deviation, age: 29.4±5.9 years; body mass: 77.7±4.1 kg) participated in the cross‐over 5 days bed rest study with three interventions: control (CON), standing (STA) and locomotion replacement training (LRT). Serum samples were taken before, during, and after bed rest. Biomarker concentrations were measured using commercial enzyme‐linked immunosorbent assays. Cartilage oligomeric matrix protein (COMP) levels after 24hrs of bed rest decreased independently of the intervention (‐16.8 to ‐9.8%) and continued to decreased until 72hrs of bed rest (minimum, ‐23.2 to ‐20.6%). LRT and STA did not affect COMP during bed rests (p=0.056) but there was a strong tendency for a slower decrease with LRT (‐9.4%) and STA (‐11.7%) compared to CON (‐16.8%). MMP‐3 levels decreased within the first 24hrs of bed rest (CON: ‐22.3%; STA: ‐14.7%; LRT: ‐17%) without intervention effect. Both COMP and MMP‐3 levels recovered to baseline levels during the 6 days recovery period. MMP‐1, MMP‐9 and TNF‐alpha levels were not affected by immobilization or intervention. COMP and MMP‐3 are mechanosensitive cartilage biomarkers affected by immobilization, and simple interventions such as standing upright or LRT during bed rest cannot prevent these changes.
Clinical significance: Simple locomotion interventions cannot prevent cartilage biomarker change during bed rest.
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... Immobilization, limited weight-bearing and bed rest are key triggers of articular cartilage atrophy (Eckstein, Hudelmaier, & Putz, 2006;Hinterwimmer et al., 2004;Hudelmaier, Glaser, Hausschild, Burgkart, & Eckstein, 2006;Liphardt et al., 2009;Vanwanseele, Eckstein, et al., 2002). Evans, Eggers, Butler, and Blumel (1960) reported that prolonged immobilization of rat knee joints caused major cartilage alterations, including matrix fibrillation, cleft formation, and ulceration. ...
... Furthermore, it is well established that muscular atrophy and osteopenia have been identified as predominant musculoskeletal complications of human space habitation (Berg, Eiken, Miklavcic, & Mekjavic, 2007). In contrast, evidence demonstrating the responses of cartilage and subchondral bone under bed rest conditions is lacking (Liphardt et al., 2009(Liphardt et al., , 2018. ...
... While biomarkers of cartilage react quickly, actual articular cartilage changes are slower and currently not the primary focus of space life sciences research. To our knowledge, there is limited evidence regarding the effect of bed rest on cartilage (Liphardt et al., 2009(Liphardt et al., , 2018. Liphardt et al. (2018) measured serum levels of COMP on days 14 and 21 of bed rest and noted that COMP decreased by 16% after 24h of bed rest and a further 5% by day 14 of bed rest, with no further change by Day 21. ...
This study assessed the influence of a 10‐day hypoxic bed rest on cartilage biomarkers and subchondral bone density across the patellofemoral joint (PFJ). Within clinical settings hypoxic tissue may arise in several types of disorders. Furthermore, a hypoxic environment is being considered for space flight habitats in the near future. Female participants (N = 12) participated in this study comprising three 10‐day interventions: hypoxic ambulation (HAMB), normoxic bed rest (NBR), and hypoxic bed rest (HBR). Venous samples were collected prior to (day −2: Pre) and during the intervention (days 2 and 5), immediately before reambulation (D11) and 24 hr post intervention (R1). Blood samples were analyzed for: aggrecan, hyaluronan, Type IIA procollagen amino terminal propeptide (PIIANP), and cartilage oligomeric matrix protein (COMP). Total bone mineral density (BMD) in eight regions (2 mm × 10 mm) across the PFJ was determined. The three interventions (HAMB, HBR, and NBR) did not induce any significant changes in the cartilage biomarkers of hyaluronan or PIIANP. Aggrecan increased during the HAMB trial to 2.02 fold the Pre value. COMP decreased significantly in both NBR & HBR compared to HAMB on D5. There were significant differences in BMD measured across the PFJ from cortical patellar bone (735 to 800 mg/cm3) to femur trabecular (195 to 226 mg/cm3). However, there were no significant changes in BMD from Pre to Post bed rest. These results indicate that there were no significant detectable effects of inactivity/unloading on subchondral bone density. The biomarker of cartilage, COMP, decreased on D5, whereas the addition of hypoxia to bed rest had no effect, it appears that hypoxia in combination with ambulation counteracted this decrease. Xxxx.
... In addition to this, if 'underloading', i.e., being sedentary is also linked to developing osteoarthritis, perhaps this also influences the expression of osteoarthritis joint biomarkers? Studies investigating joint underloading have observed thinning of articular cartilage, with decreases in COMP, proteoglycan content, and hyaluronan, though collagen was found more resistant to change (Vanwanseele et al. 2002;Liphardt et al. 2009Liphardt et al. , 2015Fig. 2 Promising biomarkers previously used to investigate acute and chronic joint loading. All biomarkers are serum unless stated. ...
... However, there are limited studies of the effect of exercise training on COMP and other biomarkers indicating cartilage metabolism. Studies of COMP in healthy individuals have investigated the effects of vibration training (Liphardt et al. 2009), collegiate soccer training (Hoch et al. 2012), and swimming and cycling training (Celik et al. 2013). In the study by Liphardt et al. (2009), the effects of immobilisation did not appear to be offset by vibration training twice per day for 2 weeks. ...
... Studies of COMP in healthy individuals have investigated the effects of vibration training (Liphardt et al. 2009), collegiate soccer training (Hoch et al. 2012), and swimming and cycling training (Celik et al. 2013). In the study by Liphardt et al. (2009), the effects of immobilisation did not appear to be offset by vibration training twice per day for 2 weeks. COMP reduced significantly in both 'bed rest' and 'bed rest with vibration training' groups, leading to the suggestion that increases in COMP requires movement as well as loading per se. ...
Purpose
The benefits of exercise across the lifespan and for a wide spectrum of health and diseases are well known. However, there remains less clarity as to the effects of both acute and chronic exercise on joint health. Serum biomarkers of joint metabolism are sensitive to change and have the potential to differentiate between normal and adverse adaptations to acute and chronic load. Therefore, the primary objective of this review is to evaluate how serum biomarkers can inform our understanding of how exercise affects joint metabolism.
Methods
A comprehensive literature search was completed to identify joint biomarkers previously used to investigate acute and chronic exercise training.
Results
Identified biomarkers included those related to joint cartilage, bone, synovium, synovial fluid, and inflammation. However, current research has largely focused on the response of serum cartilage oligomeric matrix protein (COMP) to acute loading in healthy young individuals. Studies demonstrate how acute loading transiently increases serum COMP (i.e., cartilage metabolism), which is mostly dependent on the duration of exercise. This response does not appear to be associated with any lasting deleterious changes, cartilage degradation, or osteoarthritis.
Conclusion
Several promising biomarkers for assessing joint metabolism exist and may in future enhance our understanding of the physiological response to acute and chronic exercise. Defining ‘normal’ and ‘abnormal’ biomarker responses to exercise and methodological standardisation would greatly improve the potential of research in this area to understand mechanisms and inform practice.
... [25][26][27] A previous bed rest study has shown that serum COMP concentration decreases during 14 days of immobilization. 28 However, to date the effects of bed rest on other cartilage biomarkers and the effect of bed rest exceeding 14 days on COMP is unknown. ...
... The results of our study support previous findings 28 that HDT-BR leads to an immediate reduction in serum COMP concentration. COMP levels recovered to baseline immediately after the unloading period during 21 days of HDT-BR. ...
... COMP levels recovered to baseline immediately after the unloading period during 21 days of HDT-BR. As suggested previously, 28 this finding may reflect a change in diffusion patterns due to reduced mechanical loading ...
... [25][26][27] A previous bed rest study has shown that serum COMP concentration decreases during 14 days of immobilization. 28 However, to date the effects of bed rest on other cartilage biomarkers and the effect of bed rest exceeding 14 days on COMP is unknown. ...
... The results of our study support previous findings 28 that HDT-BR leads to an immediate reduction in serum COMP concentration. COMP levels recovered to baseline immediately after the unloading period during 21 days of HDT-BR. ...
... COMP levels recovered to baseline immediately after the unloading period during 21 days of HDT-BR. As suggested previously, 28 this finding may reflect a change in diffusion patterns due to reduced mechanical loading of the lower limb in HDT-BR. Previous studies 29 have shown that serum COMP levels are sensitive to the loading mode of physical activity and that, for instance, slow but deep knee bends do not affect COMP levels. ...
The objective of the study was to test the hypothesis that serum levels of cartilage oligomeric matrix protein (COMP) would decrease and serum levels of tumor-necrosis factor alpha (TNF-α) and selected matrix metalloproteinases (MMPs) would increase in response to bed rest (BR) and that these changes are unaffected by the intake of potassium bicarbonate or whey protein. Seven and nine healthy male subjects participated in two 21-day 6° head down tilt crossover BR-studies with nutrition interventions. Serum samples were taken before, during, and after BR and biomarker concentrations were measured using commercial enzyme-linked immunosorbent assays. MMP-3 during BR was significantly lower than at baseline (reduction greater 20%; p < 0.001). MMP-3 increased significantly from 14 to 21 days of BR (+7%; p = 0.049). COMP during BR was significantly lower than at baseline (reduction greater 20%; p < 0.001). MMP-3 and COMP returned to baseline within 1 day after BR. MMP-9 on day 3 of BR was significantly lower than at baseline (-31%; p < 0.033) and on days 3, 5, and 14 of BR significantly lower than at the end of and after BR (reduction greater 35%; p < 0.030). The nutritional countermeasures did not affect these results. The observed changes in cartilage biomarkers may be caused by altered cartilage metabolism in response to the lack of mechanical stimulus during BR and inflammatory biomarkers may play a role in changes in biomarker levels.
Clinical relevance:
Immobilization independently from injury can cause altered cartilage biomarker concentration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1465-1471, 2018.
... In 2009, Liphardt et al. [109] published the first data on COMP concentration during 14 days of immobilization by 6 degrees-head-down-tilt bedrest in healthy male participants. COMP concentrations decreased dramatically in the first 48 hours of bedrest with stable COMP concentrations throughout the 14-day bedrest. ...
... The bedrest studies described in Section 21.3.2.2.1 in the context of space flight research are often crossover designed and investigate the countermeasure effect of exercise or nutrition interventions during bedrest compared to bedrest immobilization alone. Interventions that have been applied in combination with 6 degrees-head-down-tilt bedrest comprise locomotion replacement training and standing intervention in a 5 days bedrest study [108], whole body vibration training (10 3 1 minute at 20 Hz, no additional exercise) in a 14 days bedrest study [109], whey protein or bicarbonate supplementation [107] or whey and bicarbonate supplementation combined with an exercise intervention [119]. None of the investigated countermeasures affected cartilage blood biomarker concentrations [COMP, MMP-3, MMP-9, tumor necrosis factor (TNF-α)]. ...
In this chapter, we provide a critical overview of existing in vivo models for human articular cartilage mechanosensitivity based on studies investigating the response of biochemical markers (biomarkers) of articular cartilage health to acute mechanical stimuli and interventions, including loading stress, immobilization, micro- gravity, and medical interventions. We also make specific recommendations for their suitability for and application in basic research and treatment development.
... Articular cartilage, and thus joint health, is essential for the ability to move. Cartilage degradation increases during immobilisation [35][36][37][38][39] , and cartilage atrophy and loss of function may become more significant with increasing mission duration. Clinical studies have shown cartilage atrophy as a result of immobilization 40 or paralysis 41 , results supported by animal studies [42][43][44][45][46][47][48][49][50] . ...
... Importantly, cartilage regeneration and repair capacity are limited, which requires a comprehensive definition of adequate countermeasures. Indeed, research on exercise countermeasures to prevent cartilage degeneration is inconclusive 51 , and current countermeasures investigated during bed rest seem unable to prevent the effects of immobilization on cartilage biomarkers [36][37][38] . ...
Based on the European Space Agency (ESA) Science in Space Environment (SciSpacE) community White Paper “Human Physiology – Musculoskeletal system”, this perspective highlights unmet needs and suggests new avenues for future studies in musculoskeletal research to enable crewed exploration missions. The musculoskeletal system is essential for sustaining physical function and energy metabolism, and the maintenance of health during exploration missions, and consequently mission success, will be tightly linked to musculoskeletal function. Data collection from current space missions from pre-, during-, and post-flight periods would provide important information to understand and ultimately offset musculoskeletal alterations during long-term spaceflight. In addition, understanding the kinetics of the different components of the musculoskeletal system in parallel with a detailed description of the molecular mechanisms driving these alterations appears to be the best approach to address potential musculoskeletal problems that future exploratory-mission crew will face. These research efforts should be accompanied by technical advances in molecular and phenotypic monitoring tools to provide in-flight real-time feedback.
... In vivo assessment of these interactions in human articular cartilage can only be made by measurements of surrogates of cartilage metabolism (blood markers and urine markers) and estimations of ambulatory load. Several studies 16,21,[40][41][42][43][44] have investigated the effects of ambulatory exercises (walking, running, marathon and ultramarathon) or immobilization on blood levels of candidate surrogates for cartilage metabolism. All previous studies reported biomarker kinetics during and up to at least 1 hour after the exercise bout. ...
... The response of biomarkers to an exposure like a stress test is typically assessed by the change in the measured values from pre-stress test to post-stress test at the individual level. However, there are two ways to assess the change: we can consider the absolute change or the relative change compared to the pre-stress test measurements, and both approaches can be found in the literature 16,21,[40][41][42][43][44] . Relative changes have the advantage that they take into account that changes are often roughly proportional to the pre-stress test value. ...
Purpose: To determine the suitability of selected blood biomarkers of articular cartilage as mechanosensitive markers and to investigate the dose-response relationship between ambulatory load magnitude and marker kinetics in response to load.
Methods: Serum samples were collected from 24 healthy volunteers before and at three time points after a 30-minute walking stress test performed on three test days. In each experimental session, one of three ambulatory loads was applied: 100% body weight (BW); 80%BW; 120%BW. Serum concentrations of COMP, MMP-3, MMP-9, ADAMTS-4, PRG-4, CPII, C2C and IL-6 were assessed using commercial enzyme-linked immunosorbent assays. A two-stage analytical approach was used to determine the suitability of a biomarker by testing the response to the stress test (criterion I) and the dose-response relationship between ambulatory load magnitude and biomarker kinetics (criterion II).
Results . COMP, MMP-3 and IL-6 at all three time points after, MMP-9 at 30 and 60 minutes after, and ADAMTS-4 and CPII at immediately after the stress test showed an average response to load or an inter-individual variation in response to load of up to 25% of pre-test levels. The relation to load magnitude on average or an inter-individual variation in this relationship was up to 8% from load level to load level. There was a positive correlation for the slopes of the change-load relationship between COMP and MMP-3, and a negative correlation for the slopes between COMP, MMP-3 and IL-6 with MMP-9, and COMP with IL6.
Conclusions: COMP, MMP-3, IL-6, MMP-9, and ADAMTS-4 warrant further investigation in the context of articular cartilage mechanosensitivity and its role in joint degeneration and OA. While COMP seems to be able to reflect a rapid response, MMP-3 seems to reflect a slightly longer lasting, but probably also more distinct response. MMP-3 showed also the strongest association with the magnitude of load.
... Furthermore, weight-bearing articular cartilage of mice shows degradative changes in response to microgravity (Fitzgerald et al., 2019). Moreover, recent studies in humans have revealed that bed rest (Liphardt et al., 2009(Liphardt et al., , 2016(Liphardt et al., , 2018 and microgravity (Niehoff et al., 2016) may initiate catabolic processes indicated by serum biomarkers of articular cartilage metabolism. ...
... Fourteen days of bed rest, an analog that can simulate some of the adaptational processes of space flight, lead to an average reduction of serum COMP level of −14.8% that recovered to baseline levels after being mobile again. In the same study, cartilage thickness decreased by 8.3% in the loaded region of the tibia compared from before to after bed rest (Liphardt et al., 2009). ...
Microgravity during long-term space flights induces degeneration of articular cartilage. Artificial gravity through centrifugation combined with exercise has been suggested as a potential countermeasure for musculoskeletal degeneration. The purpose of this study was to investigate the effect of different types of impact loading under normal and artificial gravity conditions on serum concentrations of cartilage oligomeric matrix protein (COMP), a biomarker of cartilage metabolism. Fifteen healthy male adults (26 ± 4 years, 181 ± 4 cm, 77 ± 6 kg) performed four different 30-min impact loading protocols on four experimental days: jumping with artificial gravity elicited by centrifugation in a short-arm centrifuge (AGJ), jumping with artificial gravity generated by low-pressure cylinders in a sledge jump system (SJS), vertical jumping under Earth gravity (EGJ), and running under Earth gravity (RUN). Five blood samples per protocol were taken: 30 min before, immediately before, immediately after, 30 min after, and 60 min after impact loading. Serum COMP concentrations were analyzed in these samples. During the impact exercises, ground reaction forces were recorded. Peak ground reaction forces were significantly different between the three jumping protocols (p < 0.001), increasing from AGJ (14 N/kg) to SJS (22 N/kg) to EGJ (29 N/kg) but were similar in RUN (22 N/kg) compared to SJS. The serum COMP concentration was increased (p < 0.001) immediately after all loading protocols, and then decreased (p < 0.001) at 30 min post-exercise compared to immediately after the exercise. Jumping and running under Earth gravity (EGJ and RUN) resulted in a significantly higher (p < 0.05) increase of serum COMP levels 30 min after impact loading compared to the impact loading under artificial gravity (RUN +30%, EGJ +20%, AGJ +17%, and SJS +13% compared to baseline). In conclusion, both the amplitude and the number of the impacts contribute to inducing higher COMP responses and are therefore likely important factors affecting cartilage metabolism. RUN had the largest effect on serum COMP concentration, presumably due to the high number of impacts, which was 10 times higher than for the jump modalities. Future studies should aim at establishing a dose-response relationship for different types of exercise using comparable amounts of impacts.
... Furthermore, weight-bearing articular cartilage of mice shows degradative changes in response to microgravity (Fitzgerald et al., 2019). Moreover, recent studies in humans have revealed that bed rest (Liphardt et al., 2009(Liphardt et al., , 2016(Liphardt et al., , 2018 and microgravity (Niehoff et al., 2016) may initiate catabolic processes indicated by serum biomarkers of articular cartilage metabolism. ...
... Fourteen days of bed rest, an analog that can simulate some of the adaptational processes of space flight, lead to an average reduction of serum COMP level of −14.8% that recovered to baseline levels after being mobile again. In the same study, cartilage thickness decreased by 8.3% in the loaded region of the tibia compared from before to after bed rest (Liphardt et al., 2009). ...
Microgravity during long-term space flights induces degeneration of articular cartilage. Artificial gravity through centrifugation combined with exercise has been suggested as a potential countermeasure for musculoskeletal degeneration. The purpose of this study was to investigate the effect of different types of impact loading under normal and artificial gravity conditions on serum concentrations of cartilage oligomeric matrix protein (COMP), a biomarker of cartilage metabolism. Fifteen healthy male adults (26 ± 4 years, 181 ± 4 cm, 77 ± 6 kg) performed four different 30-min impact loading protocols on four experimental days: jumping with artificial gravity elicited by centrifugation in a short-arm centrifuge (AGJ), jumping with artificial gravity generated by low-pressure cylinders in a sledge jump system (SJS), vertical jumping under Earth gravity (EGJ), and running under Earth gravity (RUN). Five blood samples per protocol were taken: 30 min before, immediately before, immediately after, 30 min after, and 60 min after impact loading. Serum COMP concentrations were analyzed in these samples. During the impact exercises, ground reaction forces were recorded. Peak ground reaction forces were significantly different between the three jumping protocols (p < 0.001), increasing from AGJ (14 N/kg) to SJS (22 N/kg) to EGJ (29 N/kg) but were similar in RUN (22 N/kg) compared to SJS. The serum COMP concentration was increased (p < 0.001) immediately after all loading protocols, and then decreased (p < 0.001) at 30 min post-exercise compared to immediately after the exercise. Jumping and running under Earth gravity (EGJ and RUN) resulted in a significantly higher (p < 0.05) increase of serum COMP levels 30 min after impact loading compared to the impact loading under artificial gravity (RUN +30%, EGJ +20%, AGJ +17%, and SJS +13% compared to baseline). In conclusion, both the amplitude and the number of the impacts contribute to inducing higher COMP responses and are therefore likely important factors affecting cartilage metabolism. RUN had the largest effect on serum COMP concentration, presumably due to the high number of impacts, which was 10 times higher than for the jump modalities. Future studies should aim at establishing a dose-response relationship for different types of exercise using comparable amounts of impacts.
... On the other side, decreasing sCOMP was found in response to immobilization. Again, even healthy individuals show significantly decreased sCOMP after extended bed rest [32,33]. However, the time course of sCOMP after total joint replacement has never been analyzed systematically. ...
... The results of the present study suggest that there are further influences on the release of COMP from the extracellular cartilage matrix. Liphardt et al. [32,33] who investigated sCOMP in bed rest studies could detect a reduced sCOMP due to immobilization and thus lacking mechanical loading of the tissue. The decrease in sCOMP observed in our study 7 days after surgery may indicate that limited mobility and reduced Table 4 Pearson correlation coefficients (r) and p-Values (in parenthesis) for absolute sCOMP and kinetic gait parameters during the stance phase of gait (n ¼ 9 patients). ...
Objective
To study the effect of total hip replacement (THR) on serum cartilage oligomeric matrix protein concentration (sCOMP) and its correlation with joint loading during gait in patients with unilateral hip osteoarthritis.
Design
In this prospective multimodal (clinical, biomechanical, biochemical) study blood samples from 15 patients were taken before and up to three times after THR (7 days, 3 months and 1 year), each after a resting period of at least 30 min, for analysis of sCOMP. Gait analysis was performed before and 1 year after THR to determine hip and knee joint moments.
Results
Seven days after THR, sCOMP decreased significantly compared to the preoperative measurement (p < 0.001). Three months and 1 year postoperatively, sCOMP reverted to concentrations in the range of the preoperative value. One year postoperatively, a linear correlation between sCOMP and the maximum hip flexion moment was indicated in the first half of the stance phase on the unaffected side (r = −0.736, p = 0.024). No further correlations could be determined.
Conclusions
Surprisingly, the removal of a joint affected by osteoarthritis did not have a sustained effect on sCOMP. Both before and after THR there was no scientifically substantiated correlation between sCOMP and joint moments from gait analysis. Consequently, the examination of sCOMP is not useful to detect altered joint loads that may influence degenerative changes of adjacent joints after THR.
The registration number in the German Registry of Clinical Trials is DRKS00015053.
... Joint loading on Earth is necessary to maintain structural integrity, proper function and homeostasis of cartilage and other tissues constituting load-bearing synovial joints (1,2). Thus, the reduced weight bearing experienced with spaceflight represents a substantial challenge to maintaining the health of synovial joints (3)(4)(5)(6). Clinically relevant structural degradation of cartilage has been documented after periods of prescribed partial-or nonweight-bearing (3)(4)(5). Radiation, a frequently undetermined threat present during spaceflight, also affects joint health and induces an arthritic phenotype, observed at higher doses in clinical applications (7)(8)(9)(10), and at lower doses in preclinical studies (7)(8)(9)(10). ...
... Thus, the reduced weight bearing experienced with spaceflight represents a substantial challenge to maintaining the health of synovial joints (3)(4)(5)(6). Clinically relevant structural degradation of cartilage has been documented after periods of prescribed partial-or nonweight-bearing (3)(4)(5). Radiation, a frequently undetermined threat present during spaceflight, also affects joint health and induces an arthritic phenotype, observed at higher doses in clinical applications (7)(8)(9)(10), and at lower doses in preclinical studies (7)(8)(9)(10). Chronic knee damage has been observed in rats after acute exposure to 1 Gy X rays (6), which is relevant to spaceflight scenarios (e.g., solar flare). ...
Reduced weight bearing, and to a lesser extent radiation, during spaceflight have been shown as potential hazards to astronaut joint health. These hazards combined effect to the knee and hip joints are not well defined, particularly with low-dose exposure to radiation. In this study, we examined the individual and combined effects of varying low-dose radiation (≤1 Gy) and reduced weight bearing on the cartilage of the knee and hip joints. C57BL/6J mice (n = 80) were either tail suspended via hindlimb unloading (HLU) or remained full-weight bearing (ground). On day 6, each group was divided and irradiated with 0 Gy (sham), 0.1 Gy, 0.5 Gy or 1.0 Gy (n = 10/group), yielding eight groups: ground-sham; ground-0.1 Gy; ground-0.5 Gy; ground-1.0 Gy; HLU-sham; HLU-0.1 Gy; HLU-0.5 Gy; and HLU-1.0 Gy. On day 30, the hindlimbs, hip cartilage and serum were collected from the mice. Significant differences were identified statistically between treatment groups and the ground-sham control group, but no significant differences were observed between HLU and/or radiation groups. Contrast-enhanced micro-computed tomography (microCECT) demonstrated decrease in volume and thickness at the weight-bearing femoral-tibial cartilage-cartilage contact point in all treatment groups compared to ground-sham. Lower collagen was observed in all groups compared to ground-sham. Circulating serum cartilage oligomeric matrix protein (sCOMP), a biomarker for ongoing cartilage degradation, was increased in all of the irradiated groups compared to ground-sham, regardless of unloading. Mass spectrometry of the cartilage lining the femoral head and subsequent Ingenuity Pathway Analysis (IPA) identified a decrease in cartilage compositional proteins indicative of osteoarthritis. Our findings demonstrate that both individually and combined, HLU and exposure to spaceflight relevant radiation doses lead to cartilage degradation of the knee and hip with expression of an arthritic phenotype. Moreover, early administration of low-dose irradiation (0.1, 0.5 or 1.0 Gy) causes an active catabolic response in cartilage 24 days postirradiation. Further research is warranted with a focus on the prevention of cartilage degradation from long-term periods of reduced weight bearing and spaceflight-relevant low doses and qualities of radiation.
... Another aspect that has been addressed in a more limited manner in the literature is the effect of vibration on cartilage 18 , While some work has suggested positive effects of vibration to cartilage in humans 16 other work has suggested a potential to enhance degenerative effects 20 or no effect 21 in vivo in mouse models. ...
... The lack of a significant increase in cartilage thickness in the vibrated animals compared to the controls contradicts previously reported work that vibration training can improve cartilage thickness during bed-rest immobilization 18 . From our preliminary analysis, the greater cartilage thickness observed with the vibration groups does not appear to be due to a repair response to damage as evidenced by the similar histopathology scores found in the vibrated and control groups. ...
Objective
This study assessed femur properties in 80 adult female rats exposed to a range of whole body vibration amplitudes at 45 Hz over five weeks. Our hypothesis was that an optimal amplitude for whole body vibration would be apparent and would result in increased bone strength.
Methods
Animals were treated in five amplitude groups (0 g, 0.15 g, 0.3 g, 0.6 g, and 1.2 g peak), for 15 minutes per day, five days per week, for five weeks. Femur strength was assessed via: (1) three-point bending of the shaft, (2) cantilever bending of the neck, and (3) indentation of distal cancellous bone. Femoral bone mineral density, plasma prostaglandin E2 (PGE2) concentrations, cartilage thickness, and histopathologic properties were measured.
Results
Vibration doubled (P=0.039) cancellous bone stiffness in the 0.6 g and 1.2 g groups and induced a 74% increase in PGE2 concentrations (P=0.007). However, femoral densitometry and strength of the neck and shaft were unchanged and the cancellous bone indentation strength did not differ statistically (P=0.084). Cartilage thickness of vibrated groups at the medial condyle did not increase significantly (P=0.142) and the histopathologic grade did not change. There was no definitive optimal vibration amplitude.
Conclusion
The benefits of vibration therapy over five weeks were confined to cancellous bone.
... Researchers have started to explore the possibility that WBV combined with exercise and physical therapies may offer benefits to patients with KOA, including muscle strength [8], balance control [9], and decreased self-perception of pain [9]. Additionally, previous studies found that mechanical stimulation not only increased matrix accumulation and decreased matrix metalloproteinase production in osteoarthritic chondrocytes [10], but also enhanced collagen and chondrogenic marker expression in normal cartilage [11]. ...
... Zafar H. et al. conducted a systematic review and meta-analysis suggesting that WBV training reduces pain and improves function in individuals with KOA [39]. In our study, a moderate function change was observed in the lower frequency groups, which means that the effect of WBV in this OA model was frequencydependent, and suggested that the lower frequency (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) can improve function and decrease pain. ...
Backgroud
Whole-body vibration(WBV) has been suggested for the prevention of subchondral bone loss of knee osteoarthritis (OA) . This study examined the effects of different frequency of whole-body vibration on subchondral trabecular bone microarchitecture, cartilage degradation and metabolism of the tibia and femoral condyle bone, and joint pain in an anterior cruciate ligament transection (ACLT)–induced knee osteoarthritisrabbit model.
Method
Ninety adult rabbits were divided into six groups: all groups received unilateral ACLT; Group 1, ACLT only; Group 2, 5 Hz WBV; Group 3, 10 Hz WBV; Group 4, 20 Hz WBV; Group 5, 30 Hz WBV; and Group 6, 40 Hz WBV. Pain was tested via weight-bearing asymmetry. Subchondral trabecular bone microarchitecture was examined using in vivo micro-computed tomography. Knee joint cartilage was evaluated by gross morphology, histology, and ECM gene expression level (aggrecan and type II collagen [CTX-II]). Serum bone-specific alkaline phosphatase, N-mid OC, cartilage oligometric protein, CPII, type I collagen, PIIANP, G1/G2 aggrecan levels, and urinary CTX-II were analyzed.
Results
After 8 weeks of low-magnitude WBV, the lower frequency (10 Hz and 20 Hz) WBV treatment decreased joint pain and cartilage resorption, accelerated cartilage formation, delayed cartilage degradation especially at the 20 Hz regimen. However, the higher frequencies (30 Hz and 40 Hz) had worse effects, with worse limb function and cartilage volume as well as higher histological scores and cartilage resorption. In contrast, both prevented loss of trabeculae and increased bone turnover. No significant change was observed in the 5 Hz WBV group.
Conclusion
Our data demonstrate that the lower frequencies (10 Hz and 20 Hz) of low-magnitude WBV increased bone turnover, delayed cartilage degeneration, and caused a significant functional change of the OA-affected limb in ACLT-induced OA rabbit model but did not reverse OA progression after 8 weeks of treatment.
... Cartilage health of the lower limb joints has been investigated in microgravity analogue bed rest studies. Fourteen days of bed rest reduced cartilage thickness at the knee, as well as serum oligomeric matrix protein (COMP) concentrations (Liphardt et al. 2009). Furthermore, it has been shown that COMP, matrix-metalloprotease-3 (MMP 1 -3) and matrix-metalloprotease-9 (MMP-9), were sensitive to 5-and 21-days of bed rest. ...
... Furthermore, it has been shown that COMP, matrix-metalloprotease-3 (MMP 1 -3) and matrix-metalloprotease-9 (MMP-9), were sensitive to 5-and 21-days of bed rest. These results indicate that a cartilage response to unloading can be seen after as little as 1 to 2 weeks of immobilization (Liphardt 2015) Applied CM in bed rest studies, such as vibration training with (Liphardt 2015) or without (Liphardt et al. 2009) additional resistive exercise have not successfully compensated for the effects of immobilisation on cartilage metabolism. The effects of microgravity on cartilage health in humans are only just being investigated in ISS experiments. ...
This report outlines the work undertaken by the ESA Post-Mission Exercise (Reconditioning) Topical Team to ascertain and provide details of evidence based postflight reconditioning programmes, looking beyond current practices in readiness for future longer duration missions. The report covers gaps in knowledge and proposes how terrestrial rehabilitation practices, and research and development, may have lessons for post-space mission reconditioning. Information is presented to help protect astronauts from the potential long-term effects of their occupation, i.e. periodic but regular deconditioning and exposure to microgravity, and how these factors might impact the long-term risk and incidence of osteoporosis, osteoarthritis, and other conditions related to deconditioning or premature ageing. The report culminates in conclusions and recommendations for the future activities that the European Space Agency and the wider space community might pursue in preparation for long duration exploration missions.
... Insbesondere die P1NP-Konzentration blieb unbeeinflusst. Andererseits verhinderte das Vibrationstraining die durch die Bettruhe verursachte Verringerung der Knorpeldicke am Knie [36]. Leider liegen aus dieser Studie keine Daten zur Muskelfunktion oder zu kardiovaskulären Auswirkungen vor. ...
... After ACL injury, resting sCOMP concentration was higher than in an age, sex and activity level matched control group [69]. In healthy persons, sCOMP increased temporarily after walking [70][71][72] and decreased during immobilization [73][74][75]. Furthermore, post walking stress sCOMP levels correlated with long-term changes in cartilage thickness in the medial femur [76] and tibia [76,77]. ...
Objective
To describe a study protocol for investigating the in vivo dose-response relationship between ambulatory load magnitude and mechanosensitive blood markers of articular cartilage, the influence of age, cartilage tissue health and presence of inflammation on this relationship, and its ability to predict changes in articular cartilage quality and morphology within 2 years.
Design
Prospective experimental multimodal (clinical, biomechanical, biological) data collection under walking stress and three different load conditions varied in a randomized crossover design.
Experimental protocol
At baseline, equal numbers of healthy and anterior cruciate ligament injured participants aged 20–30 or 40–60 years will be assessed clinically and complete questionnaires regarding their knee health. Biomechanical parameters (joint kinetics, joint kinematics, and surface electromyography) will be recorded while performing different tasks including overground and treadmill walking, single leg balance and hopping tasks. Magnetic resonance images (MRI) of both of knees will be obtained. On separate stress test days, participants will perform a 30-minute walking stress with either reduced (80% body weight (BW)), normal (100%BW) or increased (120%BW) load. Serum blood samples will be taken immediately before, immediately after, 30, 120 and 210 minutes after the walking stress. Concentration of articular cartilage blood biomarkers will be assessed using enzyme linked immunosorbent assays. At 24-month follow-up, participants will be again assessed clinically, undergo an MRI, complete questionnaires, and have a blood sample taken.
Conclusion
The study design provides a standardized set up that allows to better understand the influence of ambulatory load on articular cartilage biomarkers and thereby extend current knowledge on in vivo cartilage metabolism and mechanosensitivity. Further, this study will help to elucidate the prognostic value of the load-induced cartilage biomarker response for early articular cartilage degeneration.
Trial registration
The protocol was approved by the regional ethics committee and has been registered at clinicaltrials.gov ( NCT04128566 ).
... Inflammatory and joint homeostasis (anabolic and catabolic) biomarkers can be informative about the overall physiological state of a patient but are less informative for determining if a specific joint of a patient is failing to adapt to a given loading stimulus (Cattano et al., 2017b). Since metabolic changes of joint tissues begin long before the onset of structural alterations, biomarker responses to physical activity may serve as indicators of tolerance (or intolerance) to physical activity and could potentially be utilised to help in prediction of cartilage loss from post-walking (Erhart-Hledik et al., 2012) or in developing new therapeutic alternatives to maintain cartilage thickness as vibration training (Liphardt et al., 2009). ...
Objective: To determine the effect of marathon running on serum levels of inflammatory, high energy, and cartilage matrix biomarkers and to ascertain whether these biomarkers levels correlate.
Design: Blood samples from 17 Caucasian male recreational athletes at the Barcelona Marathon 2017 were collected at the baseline, immediately and 48 h post-race. Serum C reactive protein (CRP), creatin kinase (CK), and lactate dehydrogenase (LDH) were determined using an AU-5800 chemistry analyser. Serum levels of hyaluronan (HA), cartilage oligomeric matrix protein (COMP), aggrecan chondroitin sulphate 846 (CS846), glycoprotein YKL-40, human procollagen II N-terminal propeptide (PIINP), human type IIA collagen N-propeptide (PIIANP), and collagen type II cleavage (C2C) were measured by sandwich enzyme-linked immune-sorbent assay (ELISA).
Results: Medians CK and sLDH levels increased (three-fold, two-fold) post-race [429 (332) U/L, 323 (69) U/L] ( p < 0.0001; p < 0.0001) and (six-fold, 1.2-fold) 48 h post-race [658 (1,073) U/L, 218 (45) U/L] ( p < 0.0001; p < 0.0001). Medians CRP increased (ten-fold) after 48 h post-race [6.8 (4.1) mg/L] ( p < 0.0001). Mean sHA levels increased (four-fold) post-race (89.54 ± 53.14 ng/ml) ( p < 0.0001). Means PIINP (9.05 ± 2.15 ng/ml) levels increased post-race (10.82 ± 3.44 ng/ml) ( p = 0.053) and 48 h post-race (11.00 ± 2.96 ng/ml) ( p = 0.001). Mean sC2C levels (220.83 ± 39.50 ng/ml) decreased post-race (188.67 ± 38.52 ng/ml) ( p = 0.002). In contrast, means COMP, sCS846, sPIIANP, and median sYKL-40 were relatively stable. We found a positive association between sCK levels with sLDH pre-race ( r = 0.758, p < 0.0001), post-race ( r = 0.623, p = 0.008) and 48-h post-race ( r = 0.842, p < 0.0001); sHA with sCRP post-race vs. 48 h post-race ( r = 0.563, p = 0.019) and sPIINP with sCK pre-race vs. 48-h post-race ( r = 0.499, p = 0.044) and with sLDH 48-h pre-race vs. post-race ( r = 0.610, p = 0.009) and a negative correlation of sPIIANP with sCRP 48-h post-race ( r = −0.570, p = 0.017).
Conclusion: Marathon running is an exercise with high-energy demands (sCK and sLDH increase) that provokes a high and durable general inflammatory reaction (sCRP increase) and an immediately post-marathon mechanism to protect inflammation and cartilage (sHA increase). Accompanied by an increase in type II collagen cartilage fibrils synthesis (sPIINP increase) and a decrease in its catabolism (sC2C decrease), without changes in non-collagenous cartilage metabolism (sCOMP, sC846, and sYKL-40). Metabolic changes on sPIINP and sHA synthesis may be related to energy consumption (sCK, sLDH) and the inflammatory reaction (sCRP) produced.
... The blood COMP level is sensitive to physiological stress. The study of 14 day HDT BR demonstrated that the joint cartilage thickness was reduced during the experiment, followed by a decrease in the COMP level [99]. Liu et al. [100] reported the chondrocytes' ability to respond to stress in the extracellular environment (possibly both mechanical and shear stress), which resulted in an altered expression of matrix proteins. ...
Gravity is fundamental factor determining all processes of development and vital activity on Earth. During evolution, a complex mechanism of response to gravity alterations was formed in multicellular organisms. It includes the “gravisensors” in extracellular and intracellular spaces. Inside the cells, the cytoskeleton molecules are the principal gravity-sensitive structures, and outside the cells these are extracellular matrix (ECM) components. The cooperation between the intracellular and extracellular compartments is implemented through specialized protein structures, integrins. The gravity-sensitive complex is a kind of molecular hub that coordinates the functions of various tissues and organs in the gravitational environment. The functioning of this system is of particular importance under extremal conditions, such as spaceflight microgravity. This review covers the current understanding of ECM and associated molecules as the matrisome, the features of the above components in connective tissues, and the role of the latter in the cell and tissue responses to the gravity alterations. Special attention is paid to contemporary methodological approaches to the matrisome composition analysis under real space flights and ground-based simulation of its effects on Earth.
... Gravity is important for cartilage health as it provides a loading force essential for cartilage homeostasis and prevention of degenerative diseases such as OA. [66][67][68][69] Although cartilage morphology and skeletal muscle mass has been shown to be affected by altered loading conditions, [70][71][72][73] our data suggest that two days of hypergravity exposure is not sufficient to cause gross morphological changes in larval zebrafish. One explanation for this is the length of exposure being insufficient to induce musculoskeletal remodelling, as previous studies have found that longer exposure to non-Earth gravity leads to more severe musculoskeletal transformations. ...
Aims
Vertebrates have adapted to life on Earth and its constant gravitational field, which exerts load on the body and influences the structure and function of tissues. While the effects of microgravity on muscle and bone homeostasis are well described, with sarcopenia and osteoporosis observed in astronauts returning from space, the effects of shorter exposures to increased gravitational fields are less well characterized. We aimed to test how hypergravity affects early cartilage and skeletal development in a zebrafish model.
Methods
We exposed zebrafish to 3 g and 6 g hypergravity from three to five days post-fertilization, when key events in jaw cartilage morphogenesis occur. Following this exposure, we performed immunostaining along with a range of histological stains and transmission electron microscopy (TEM) to examine cartilage morphology and structure, atomic force microscopy (AFM) and nanoindentation experiments to investigate the cartilage material properties, and finite element modelling to map the pattern of strain and stress in the skeletal rudiments.
Results
We did not observe changes to larval growth, or morphology of cartilage or muscle. However, we observed altered mechanical properties of jaw cartilages, and in these regions we saw changes to chondrocyte morphology and extracellular matrix (ECM) composition. These areas also correspond to places where strain and stress distribution are predicted to be most different following hypergravity exposure.
Conclusion
Our results suggest that altered mechanical loading, through hypergravity exposure, affects chondrocyte maturation and ECM components, ultimately leading to changes to cartilage structure and function. Cite this article: Bone Joint Res 2021;10(2):137–148.
... While the current research focused on foot contact mechanics and associated OA risk, the push-off phase of the gait cycle may be equally important, with knee flexion moment considered a key kinetic marker [33]. Connective tissues such as ligaments should also be taken into account to fully describe the causes of OA and in terms of recovery, cartilage resynthesis in addition to mechanical factors relating to OA risks should be the essential aspect [8,34]. ...
The prevalence of knee osteoarthritis (OA) increases with ageing and this research aimed to identify gait adaptations that could reduce OA by investigating ageing effects on knee joint biomechanics. Participants were 24 healthy young males (18–35 yrs) and 14 healthy older males (60–75 yrs). Three-dimensional motion capture (Optotrak) and walkway-embedded force plates (AMTI) recorded their natural preferred-speed walking and the following parameters were computed: knee adduction moment, knee joint vertical force, foot contact angle, toe-out angle, foot centre of pressure displacement, time to foot flat, step length, step width and double support time. A 2 × 2 (age × limb) repeated measures mixed model analysis of variance design determined main effects and interactions. Pearson’s correlations between knee kinetic parameters and stride phase variables were also calculated. Both knee adduction moment and vertical joint force were larger in the older group. Relative to the young controls, older individuals showed a longer time to foot flat, less toe-out angle and wider steps. Correlation analysis suggested that reduced toe-out angle and increased step width were associated with lower knee adduction moment; furthermore, knee joint vertical force reduced with greater step length. Future research could focus on intervention strategies for managing excessive knee joint stresses to prevent the ageing-related development of knee OA.
... In particular, P1NP levels were un-affected. On the other hand, vibration training prevented bed rest-induced reduction in cartilage thickness at the knee [36]. Unfortunately, no data on muscle function or on cardiovascular effects are available from that study. ...
Whole-body vibration exercise has been tested as a countermeasure against deterioration of body systems in spaceflight simulation (bed rest). The first Berlin BedRest Study demonstrated that resistive vibration exercise (RVE) can reduce muscle loss, prevent muscle weakness, prevent bone loss, and ameliorate pain during post–bed rest recovery as well as prevent or reduce changes in other body systems. A limitation of this study was the inability to determine the contribution of WBV in addition to resistance exercise (RE). The second Berlin BedRest Study showed that adding WBV to RE resulted in better efficacy to prevent bone loss, whereas RE and RVE were equivocal in reducing or preventing muscle atrophy. There was some evidence of an additional effect of WBV in modulating body composition changes when added to RE. Successful countermeasure exercise with WBV is possible when performed vigorously, i.e. with large loading force, and with more than three exercise sessions per week.
... We also sought to identify gait alterations that are reflective of joint (cartilage) degradation, a known response of knees to reduced weight bearing (Liphardt et al., 2009;Willey et al., 2016). Some patterns of gait change in rodents reflect musculoskeletal deficits, a well-described consequence of prolonged periods of reduced weight bearing in mice (Bateman et al., 2000;Lloyd et al., 2012). ...
The long-term adaptations to microgravity and other spaceflight challenges within the confines of a spacecraft, and readaptations to weight-bearing upon reaching a destination, are unclear. While post-flight gait change in astronauts have been well documented and reflect multi-system deficits, no data from rodents have been collected. Thus, the purpose of this study was to evaluate gait changes in response to spaceflight. A prospective collection of gait data was collected on 3 groups of mice: those who spent~35 days in orbit (FLIGHT) aboard the International Space Station (ISS); a ground-based control with the same habitat conditions as ISS (Ground Control; GC); and a vivarium control with typical rodent housing conditions (VIV). Pre-flight and post-flight gait measurements were conducted utilizing an optimized and portable gait analysis system (DigiGait, Mouse Specifics, Inc). The total data acquisition time for gait patterns of FLIGHT and control mice was 1.5-5 min/mouse, allowing all 20 mice per group to be assessed in less than an hour. Patterns of longitudinal gait changes were observed in the hind limbs and the forelimbs of the FLIGHT mice after ~35 days in orbit; few differences were observed in gait characteristics within the GC and VIV controls from the initial to the final gait assessment, and between groups. For FLIGHT mice, 12 out of 18 of the evaluated gait characteristics in the hind limbs were significantly changed, including: stride width variability; stride length and variance; stride, swing, and stance duration; paw angle and area at peak stance; and step angle, among others. Gait characteristics that decreased included stride frequency, and others. Moreover, numerous forelimb gait characteristics in the FLIGHT mice were changed at post-flight measures relative to pre-flight. This rapid DigiGait gait measurement tool and customized spaceflight protocol is useful for providing preliminary insight into how spaceflight could affect multiple systems in rodents in which deficits are reflected by altered gait characteristics.
... Similar to bone, insufficient loading can lead to cartilage degeneration. Patients on bed-rest experience loss of cartilage thickness after only 14 days [6]; and, muscle weakness has been associated with the progression of osteoarthritis [7,8]. However, excessive repetitive loading has been associated with chondrocyte death and cartilage degeneration [9,10]. ...
Mechanical loading is essential for the maintenance of musculoskeletal homeostasis. Cartilage has been demonstrated to be highly mechanoresponsive, but the mechanisms by which chondrocytes respond to mechanical stimuli are not clearly understood. The goal of the study was to determine how LRP4, LRP5, and LRP6 within canonical Wnt-signaling are regulated in simulated microgravity and cyclic hydrostatic pressure, and to investigate the potential role of LRP 4/5/6 in cartilage degeneration. Rat chondrosacroma cell (RCS) pellets were stimulated using either cyclic hydrostatic pressure (1Hz, 7.5 MPa, 4hr/day) or simulated microgravity in a rotating wall vessel (RWV) bioreactor (11RPM, 24hr/day). LRP4/5/6 mRNA expression was assessed by RT-qPCR and LRP5 protein expression was determined by fluorescent immunostaining. To further evaluate our in vitro findings in vivo, mice were subjected to hindlimb suspension for 14 days and the femoral heads stained for LRP5 expression. We found that, in vitro, LRP4/5/6 mRNA expression is modulated in a time-dependent manner by mechanical stimulation. Additionally, LRP5 protein expression is upregulated in response to both simulated microgravity and cyclic hydrostatic pressure. LRP5 is also upregulated in vivo in the articular cartilage of hindlimb suspended mice. This is the first study to examine how LRP4/5/6, critical receptors within musculoskeletal biology, respond to mechanical stimulation. Further elucidation of this mechanism could provide significant clinical benefit for the identification of pharmaceutical targets for the maintenance of cartilage health.
... Whole-body vibration exercise (WBVE) has become a popular modality and is found in homes, public gyms, and in the offices of various health-care professionals. WBVE can lead to improvements in strength, 1 improved bone mineral density in animal models, 2 articular cartilage in human subjects, 3 and decreased risk of falls in the elderly. 4,5 While these studies report benefits of WBVE, others have reported mixed results depending on the performance indicator. ...
Many research studies have evaluated the effects of whole-body vibration exercise on muscular strength, standing balance, and bone density, but relatively few reports have evaluated safety issues for vibration exercises. Knee flexion reduces acceleration transmission to the head during static exercise. However, few studies have evaluated dynamic exercises. The purpose of this investigation was to evaluate the transmission of acceleration to the head during dynamic squats. Twelve participants performed dynamic squats (0°-40° of knee flexion) on a synchronous vertical whole-body vibration platform. Platform frequencies from 20 to 50 Hz were tested at a peak-to-peak nominal displacement setting of 1 mm. Transmissibilities from the platform to head varied depending on platform frequency and knee flexion angle. We observed amplification during 20 and 25 Hz platform vibration when knee flexion was <20°. Vibration from exercise platforms can be amplified as it is transmitted through the body to the head during dynamic squats. Similarly, this vibration energy contributes to observed injuries such as retinal detachment. It is recommended that knee flexion angles of at least 20° and vibration frequencies above 30 Hz are used when performing dynamic squat exercises with whole-body vibration.
... [22][23][24]28,30 Moreover, during 14-day and 21-day bedrest sCOMP levels were 15% and 20% lower than before bedrest. 31,32 These previous results indicate that sCOMP is not only sensitive to physical activity and to inactivity but that the magnitude and direction of response depends on the type or duration of the activity and possibly on the load magnitude. ...
Objective:
To determine the dose-response relationship between ambulatory load magnitude during a walking stress test and load-induced changes in serum concentration of cartilage oligomeric matrix protein (sCOMP) in healthy subjects.
Design:
sCOMP was assessed before and after a 30-minute walking stress test performed on three test days by 24 healthy volunteers. In each walking stress test, one of three ambulatory loads was applied in a block randomized crossover design: normal body weight (100%BW = normal load); reduced body weight (80%BW = reduced load); increased body weight (120%BW = increased load). Knee kinematics and ground reaction force were measured using an inertial sensor gait analysis system and a pressure plate embedded in the treadmill.
Results:
Load-induced increases in sCOMP rose with increasing ambulatory load magnitude. Mean sCOMP levels increased immediately after the walking stress test by 26.8 ± 12.8%, 28.0 ± 13.3% and 37.3 ± 18.3% for the reduced, normal or increased load condition, respectively. Lower extremity kinematics did not differ between conditions.
Conclusions:
The results of this study provide important evidence of a dose-response relationship between ambulatory load magnitude and load-induced changes in sCOMP. Our data suggests that in normal weight persons sCOMP levels are more sensitive to increased than to reduced load. The experimental framework presented here may form the basis for studying the relevance of the dose-response relationship between ambulatory load magnitude and load-induced changes in biomarkers involved in metabolism of healthy articular cartilage and after injury.
... The following settings for the WBV-exercise were used: 20 Hz vibration frequency, 3 mm amplitude, ten 1-minute repetitions with intermittent 1-minute breaks without WBV. 23 After the last WBV repetition, participants remained on the plate for another 5 minutes without WBV. ...
Mechanically induced itch is an important cofactor in many patients with chronic itch. However, studying mechanical itch in a controlled environment is challenging because it is difficult to evoke. We investigated the use of whole body vibration exercise (WBV) exercise, a training method used for musculoskeletal rehabilitation, to experimentally evoke mechanical itch. Mild to severe itch ascending from the soles to the groins was evoked in 16 of 20 healthy participants. We observed a characteristic on/off itch crescendo pattern reflecting the alternating intervals of vibration and no vibration. Wheals or an angioedema were absent, and serum mast cell tryptase was not increased by the exercise. Participants described the evoked sensation primarily as “itching” with some nociceptive components. Itch intensity correlated with the intensity of a concomitant erythema (R=0.45, P=0.043) and with the rise in skin temperature (R=0.54, P=0.017). Hence, WBV can be used as an easily applicable, non‐invasive, investigator‐ and user‐friendly framework for studying mechanical itch. Moreover, WBV allows to “switch itch on and off” rapidly and to simultaneously study interactions between itch, skin blood flow and skin temperature.
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... rticular cartilage is a special connective tissue and its most important feature is to provide a lubricated surface and facilitate the delivery of the load [1]. Articular cartilage is a hydrated tissue which covers the end of femur and tibia, giving support to the knee joint in order to overcome loads due to body weight in daily activities such as standing, walking and sitting [2]. Articular cartilage composed by a porous matrix saturated with water. ...
The finite element method (FEM) is a computational technique that is often used to solve biomedical engineering problems. The biphasic cartilage model plays important role in representing the mechanical behaviour of the articular cartilage. In order to obtain accurate results in finite element analysis of articular cartilage, it is necessary to determine appropriate FEM parameters such as mesh density and finite element type. Models with small element sizes in the FEM allow more accurate results to be obtained however it requires longer calculation time. In contrast, large element size can lead to non-precision results while shortening the calculation time. The type of the elements may also change the results of FEM analysis for biomechanical problems. The purpose of this study is; to evaluate the effect of the mesh size and type of the finite element on the results of the numerical biphasic tissues. In this study, in order to achieve this goal a series of compression analyzes were performed on the 3D biomedical models with different mesh density and element types using ABAQUS 6.13 software and the results were compared. The analysis results showed that mesh density element type and element type had little effect on the maximum reaction force. On the contrary, the mesh density had greatly increased the computational time.
... The results of a 2016 hindlimb-unloading study in rats suggest that a synergistic effect exists between a reduction in weight-bearing and an increase in exposure to radiation in causing degeneration of cartilage in the knee joint 48 . During simulated weightlessness in healthy men who undertook 2 weeks of HDT bed rest, tibial cartilage thickness decreased by 8%, an effect that might be counteracted by vibration training 49 . Crucially, the interplay between cartilage, muscle and bone is now being recognized as vital to maintaining the structure and function of all musculoskeletal tissues that are needed for stature and locomotion on Earth 50 . ...
Low-orbit spaceflight induces bone fragility at weight-bearing skeletal sites and increases bone resorption.
Bone that is lost during space sojourns is not fully regained, and bone density can continue to deteriorate after landing, possibly owing to osteocyte death.
Physical activities and other interventions (known as countermeasures) designed to reduce loss of bone are not completely effective.
Cartilaginous tissues, such as intervertebral discs, lose structure and function in space and require effective countermeasures to facilitate re-adaptation to gravity upon landing.
Galactic and solar radiation in deep-space environments can contribute to bone loss, and radiation countermeasures are urgently needed.
... 22 In humans, extended bedrest has led to decreased cartilage thickness within the knee joint, an early harbinger of osteoarthritis. 23 In contrast, moderate exercise, in the form of cycling, rope skipping, and light jogging, has been shown to improve GAG content in knee cartilage of patients at high risk of developing knee OA, 24 providing evidence that some mechanical signals are better than none. Daily running in high fat diet fed mice mitigated the cartilage GAG loss and subchondral bone thickening, 7 achieved without any changes in body weight compared to the sedentary group, suggesting that dynamic mechanical signals may promote cartilage health while the absence of them are permissive to OA progression. ...
Obesity is associated with an elevated risk of osteoarthritis (OA). We examined here whether high fat diet administered in young mice, compromised the attainment of articular cartilage thickness. Further, we sought to determine if low intensity vibration (LIV) could protect the retention of articular cartilage in a mouse model of diet induced obesity. Five-week-old, male, C57BL/6 mice were separated into 3 groups (n = 10): Regular diet (RD), High fat diet (HF), and HF + LIV (HFv; 90Hz, 0.2g, 30 min/d, 5 d/w) administered for 6 weeks. Additionally, an extended HF diet study was run for 6 months (LIV at 15m/d). Articular cartilage and subchondral bone morphology, and sulfated GAG content were quantified using contrast agent enhanced µCT and histology. Gene expression within femoral condyles was quantified using real-time polymerase chain reaction. Contrary to our hypothesis, HF cartilage thickness was not statistically different from RD. However, LIV increased cartilage thickness compared to HF, and the elevated thickness was maintained when diet and LIV were extended into adulthood. RT-PCR analysis showed a reduction of aggrecan expression with high fat diet, while application of LIV reduced the expression of degradative MMP-13. Further, long term HF diet resulted in subchondral bone thickening, compared to RD, providing early evidence of OA pathology—LIV suppressed the thickening, such that levels were not significantly different from RD. These data suggest that dynamic loading, via LIV, protected the retention of cartilage thickness, potentially resulting in joint surfaces better suited to endure the risks of elevated loading that parallel obesity. This article is protected by copyright. All rights reserved
... 152,153 Likewise, the absence of mechanical stimulation, such as in cases of extended bedrest, has been shown to induce cartilage thinning. 154 Moderate exercise, however, in the form of cycling, rope skipping, and light jogging, has been shown to improve knee cartilage glycosaminoglycan content in patients at high risk of developing knee OA. 155 As with bone and muscle, previous research suggests that obesity induces degenerative changes in cartilage tissue. Although the mechanism by which obesity induces cartilage degeneration is still unclear, research suggests that altered joint biomechanics and elevated secretion of proinflammatory cytokines and adipokines contribute to increased osteoarthritis risk. ...
The incidence of obesity is rapidly rising, increasing morbidity and mortality rates worldwide. Associated comorbidities include type II diabetes, heart disease, fatty liver disease, and cancer. The impact of excess fat on musculoskeletal health is still unclear, although it is associated with increased fracture risk and a decline in muscular function. The complexity of obesity makes understanding the etiology of bone and muscle abnormalities difficult. Exercise is an effective and commonly prescribed non-pharmacological treatment option, but it can be difficult or unsafe for the frail, elderly and morbidly obese. Exercise alternatives such as low intensity vibration (LIV) have potential for improving musculoskeletal health, particularly in conditions with excess fat. LIV has been shown to influence bone marrow mesenchymal stem cell differentiation towards higher order tissues (i.e. bone) and away from fat. While the exact mechanisms are not fully understood, recent studies utilizing LIV both at the bench and in the clinic, have demonstrated its efficacy. In this review, we discuss the current literature investigating the effects of obesity on bone, muscle and bone marrow, and how exercise and LIV can be used as effective treatments for combating the negative effects in the presence of excess fat.
... 2,38 The lack of changes in MMP-1, C2C, and CPII levels and in C2C:CPII suggests that extreme running loads did not affect collagen turnover. Similarly, COMP, MMP-3, and MMP-9 but not MMP-1 levels changed in a 21-day bed rest study, 17 suggesting that MMP-1 is not sensitive to loading. ...
Background:
Cartilage turnover and load-induced tissue changes are frequently assessed by quantifying concentrations of cartilage biomarkers in serum. To date, information on the effects of ultramarathon running on articular cartilage is scarce.
Hypothesis:
Serum concentrations of cartilage oligomeric matrix protein (COMP), matrix metalloproteinase (MMP)-1, MMP-3, MMP-9, COL2-3/4C long mono (C2C), procollagen type II C-terminal propeptide (CPII), and C2C:CPII will increase throughout a multistage ultramarathon.
Study design:
Descriptive laboratory study.
Methods:
Blood samples were collected from 36 runners (4 female; mean age, 49.0 ± 10.7 years; mean body mass index, 23.1 ± 2.3 kg/m(2) [start] and 21.4 ± 1.9 kg/m(2) [finish]) before (t0) and during (t1: 1002 km; t2: 2132 km; t3: 3234 km; t4: 4039 km) a 4486-km multistage ultramarathon. Serum COMP, MMP-1, MMP-3, MMP-9, C2C, and CPII levels were assessed using commercial enzyme-linked immunosorbent assays. Linear mixed models were used to detect significant changes in serum biomarker levels over time with the time-varying covariates of body weight, running speed, and daily running time.
Results:
Serum concentrations of COMP, MMP-9, and MMP-3 changed significantly throughout the multistage ultramarathon. On average, concentrations increased during the first measurement interval (MI1: t1-t0) by 22.5% for COMP (95% CI, 0.29-0.71 ng/mL), 22.3% for MMP-3 (95% CI, 0.24-15.37 ng/mL), and 95.6% for MMP-9 (95% CI, 81.7-414.5 ng/mL) and remained stable throughout MI2, MI3, and MI4. Serum concentrations of MMP-1, C2C, CPII, and C2C:CPII did not change significantly throughout the multistage ultramarathon. Changes in MMP-3 were statistically associated with changes in COMP throughout the ultramarathon race (MMP-3: Wald Z = 3.476, P = .001).
Conclusion:
Elevated COMP levels indicate increased COMP turnover in response to extreme running, and the association between load-induced changes in MMP-3 and changes in COMP suggests the possibility that MMP-3 may be involved in the degradation of COMP.
Clinical relevance:
These results suggest that articular cartilage is able to adapt even to extreme physical activity, possibly explaining why the risk of degenerative joint disease is not elevated in the running population.
... 2,38 The lack of changes in MMP-1, C2C, and CPII levels and in C2C:CPII suggests that extreme running loads did not affect collagen turnover. Similarly, COMP, MMP-3, and MMP-9 but not MMP-1 levels changed in a 21-day bed rest study, 17 suggesting that MMP-1 is not sensitive to loading. ...
... While the extent of the damaging effects of prolonged unloading during spaceflight on the soft tissues of the knee remains unclear, considerable evidence indicates that cartilage degradation in joints occurs with reduced loading (11)(12)(13)(14). Normal loading patterns applied to the knee joint on Earth are necessary to maintain structural integrity of the cartilage, proper joint function and joint homeostasis (13,15). ...
There is little known about the effect of both reduced weight bearing and exposure to radiation during spaceflight on the mechanically-sensitive cartilage lining the knee joint. In this study, we characterized cartilage damage in rat knees after periods of reduced weight bearing with/without exposure to solar-flare-relevant radiation, then cartilage recovery after return to weight bearing. Male Sprague Dawley rats (n = 120) were either hindlimb unloaded (HLU) via tail suspension or remained weight bearing in cages (GROUND). On day 5, half of the HLU and GROUND rats were 1 Gy total-body X-ray irradiated during HLU, and half were sham irradiated (SHAM), yielding 4 groups: GROUND-SHAM; GROUND-IR; HLU-SHAM; and HLU-IR. Hindlimbs were collected from half of each group of rats on day 13. The remaining rats were then removed from HLU or remained weight bearing, and hindlimbs from these rats were collected on day 63. On day 13, glycosaminoglycan (GAG) content in cartilage lining the tibial plateau and femoral condyles of HLU rats was lower than that of the GROUND animals. Likewise, on day 13, immunoreactivity of the collagen type II-degrading matrix metalloproteinase-13 (MMP-13) and of a resultant metalloproteinase-generated neoepitope VDIPEN was increased in all groups versus GROUND-SHAM. Clustering of chondrocytes indicating cartilage damage was present in all HLU and IR groups versus GROUND-SHAM on day 13. On day 62, after 49 days of reloading, the loss of GAG content was attenuated in the HLU-SHAM and HLU-IR groups, and the increased VDIPEN staining in all treatment groups was attenuated. However, the increased chondrocyte clustering remained in all treatment groups on day 62. MMP-13 activity also remained elevated in the GROUND-IR and HLU-IR groups. Increased T2 relaxation times, measured on day 62 using 7T MRI, were greater in GROUND-IR and HLU-IR knees, indicating persistent cartilage damage in the irradiated groups. Both HLU and total-body irradiation resulted in acute degenerative and pre-arthritic changes in the knee articular cartilage of rats. A return to normal weight bearing resulted in some recovery from cartilage degradation. However, radiation delivered as both a single challenge and when combined with HLU resulted in chronic cartilage damage. These findings suggest that radiation exposure during spaceflight leads to and/or impairs recovery of cartilage upon return to reloading, generating long-term joint problems for astronauts.
... The effects of cyclic mechanical loading have been evaluated on various tissue types and vibrational therapy may provide a potent countermeasure against the effects of disuse and joint immobilization and assist in tissue healing. 101 Vibration has long been used as a method to induce muscle relaxation and overall well-being. Vibration therapy has more recently been used for neuromuscular reeducation where postural muscles make rapid and constant adjustments to the applied vibrational forces. ...
This review summarizes the current literature available on joint cartilage alterations in long-duration spaceflight. Evidence from spaceflight participants is currently limited to serum biomarker data in only a few astronauts. Findings from analogue model research, such as bed rest studies, as well as data from animal and cell research in real microgravity indicate that unloading and radiation exposure are associated with joint degeneration in terms of cartilage thinning and changes in cartilage composition. It is currently unknown how much the individual cartilage regions in the different joints of the human body will be affected on long-term missions beyond the Low Earth Orbit. Given the fact that, apart from total joint replacement or joint resurfacing, currently no treatment exists for late-stage osteoarthritis, countermeasures might be needed to avoid cartilage damage during long-duration missions. To plan countermeasures, it is important to know if and how joint cartilage and the adjacent structures, such as the subchondral bone, are affected by long-term unloading, reloading, and radiation. The use of countermeasures that put either load and shear, or other stimuli on the joints, shields them from radiation or helps by supporting cartilage physiology, or by removing oxidative stress possibly help to avoid OA in later life following long-duration space missions. There is a high demand for research on the efficacy of such countermeasures to judge their suitability for their implementation in long-duration missions.
Purpose: To determine the suitability of selected blood biomarkers of articular cartilage as mechanosensitive markers and to investigate the dose-response relationship between ambulatory load magnitude and marker kinetics in response to load.
Methods: Serum samples were collected from 24 healthy volunteers before and at three time points after a 30-minute walking stress test performed on three test days. In each experimental session, one of three ambulatory loads was applied: 100% body weight (BW); 80%BW; 120%BW. Serum concentrations of COMP, MMP-3, MMP-9, ADAMTS-4, PRG-4, CPII, C2C and IL-6 were assessed using commercial enzyme-linked immunosorbent assays. A two-stage analytical approach was used to determine the suitability of a biomarker by testing the response to the stress test (criterion I) and the dose-response relationship between ambulatory load magnitude and biomarker kinetics (criterion II).
Results . COMP, MMP-3 and IL-6 at all three time points after, MMP-9 at 30 and 60 minutes after, and ADAMTS-4 and CPII at immediately after the stress test showed an average response to load or an inter-individual variation in response to load of up to 25% of pre-test levels. The relation to load magnitude on average or an inter-individual variation in this relationship was up to 8% from load level to load level. There was a positive correlation for the slopes of the change-load relationship between COMP and MMP-3, and a negative correlation for the slopes between COMP, MMP-3 and IL-6 with MMP-9, and COMP with IL6.
Conclusions: COMP, MMP-3, IL-6, MMP-9, and ADAMTS-4 warrant further investigation in the context of articular cartilage mechanosensitivity and its role in joint degeneration and OA. While COMP seems to be able to reflect a rapid response, MMP-3 seems to reflect a slightly longer lasting, but probably also more distinct response. MMP-3 showed also the strongest association with the magnitude of load.
Chondrocytes as mechano-sensitive cells can sense and respond to mechanical stress throughout life. In chondrocytes, changes of structure and morphology in the cytoskeleton have been potentially involved in various mechano-transductions such as stretch-activated ion channels, integrins, and intracellular organelles. However, the mechanism of cytoskeleton rearrangement in response to mechanical loading and unloading remains unclear. In this study, we exposed chondrocytes to a physiological range of cyclic tensile strain as mechanical loading or to simulated microgravity by 3D-clinostat that produces an unloading environment. Based on microarray profiling, we focused on Fat1 that implicated in the formation and rearrangement of actin fibers. Next, we examined the relationship between the distribution of Fat1 proteins and actin fibers after cyclic tensile strain and microgravity. As a result, Fat1 proteins did not colocalize with actin stress fibers after cyclic tensile strain, but accumulated near the cell membrane and colocalized with cortical actin fibers after microgravity. Our findings indicate that Fat1 may mediate the rearrangement of cortical actin fibers induced by mechanical unloading.
Reduced knee weight-bearing from prescription or sedentary lifestyles are associated with cartilage degradation; effects on the meniscus are unclear. Rodents exposed to spaceflight or hind limb unloading (HLU) represent unique opportunities to evaluate this question. This study evaluated arthritic changes in the medial knee compartment that bears the highest loads across the knee after actual and simulated spaceflight, and recovery with subsequent full weight-bearing. Cartilage and meniscal degradation in mice were measured via microCT, histology, and proteomics and/or biochemically after: (1) ~ 35 days on the International Space Station (ISS); (2) 13-days aboard the Space Shuttle Atlantis; or (3) 30 days of HLU, followed by a 49-day weight-bearing readaptation with/without exercise. Cartilage degradation post-ISS and HLU occurred at similar spatial locations, the tibial-femoral cartilage-cartilage contact point, with meniscal volume decline. Cartilage and meniscal glycosaminoglycan content were decreased in unloaded mice, with elevated catabolic enzymes (e.g., matrix metalloproteinases), and elevated oxidative stress and catabolic molecular pathway responses in menisci. After the 13-day Shuttle flight, meniscal degradation was observed. During readaptation, recovery of cartilage volume and thickness occurred with exercise. Reduced weight-bearing from either spaceflight or HLU induced an arthritic phenotype in cartilage and menisci, and exercise promoted recovery.
This chapter describes a new method for pinpointing the latency of the vibration-induced muscular reflex. To determine the reflex latency, the vibration-altered electromyography (EMG) and acceleration data were spike triggered and averaged using the tip of the EMG response as the trigger. Averaged results belonging to several different vibration frequencies were then superimposed to achieve a ‘cumulative averaged record’. The lowest standard error of the cumulative averaged record for the acceleration data was marked to indicate the effective stimulus point on the vibration cycle. Similarly, the lowest standard error of the cumulative averaged record for the EMG data showed the start of the reflex response. The time between the effective stimulus point and the start of the reflex response on EMG data was designated as the ‘reflex latency’ of this circuit. Using this technique, we have examined the latency of whole-body vibration (WBV)-induced reflexes. We found that the WBV induced two different reflex responses depending on the vibration amplitude. While low amplitude WBV (0.1–0.4 mm) produced short latency reflex similar to muscle spindle-based T-reflex (34 ms), high amplitude vibration (1.1–2.8 mm) generated long latency reflex response (44 ms) which may have a different receptor origin than the spindles. We have also summarized the modulatory effects of vibration on spindle-based reflexes and indicated that these reflexes are reduced during and/or following vibration. It is suggested that this effect may originate from the reduction in effectiveness of the spindle synapses on motoneurons via premotoneuronal means.
Pulsed electromagnetic field (PEMF) and whole body vibration (WBV) interventions are expected to be important strategies for management of osteoarthritis (OA). The aim of the study was to investigate the comparative effectiveness of PEMF versus WBV on cartilage and subchondral trabecular bone in mice with knee OA (KOA) induced by surgical destabilization of the medial meniscus (DMM). Forty 12‐week‐old male C57/BL mice were randomly divided into four groups (n = 10): Control, OA, PEMF, and WBV. OA was induced (OA, PEMF, and WBV groups) by surgical DMM of right knee joint. Mice in PEMF group received 1 h/day PEMF exposure with 75 Hz, 1.6 mT for 4 weeks, and the WBV group was exposed to WBV for 20 min/day with 5 Hz, 4 mm, 0.3 g peak acceleration for 4 weeks. Micro‐computed tomography (micro‐CT), histology, and immunohistochemistry analyses were performed to evaluate the changes in cartilage and microstructure of trabecular bone. The bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) increased, and bone surface/bone volume (BS/BV) decreased by micro‐CT analysis in PEMF and WBV groups. The Osteoarthritis Research Society International (OARSI) scores in PEMF and WBV groups were significantly lower than in the OA group. Immunohistochemical results showed that PEMF and WBV promoted expressions of Aggrecan, and inhibited expressions of IL‐1β, ADAMTS4, and MMP13. Superior results are seen in PEMF group compared with WBV group. Both PEMF and WBV were effective, could delay cartilage degeneration and preserve subchondral trabecular bone microarchitecture, and PEMF was found to be superior to WBV. Bioelectromagnetics.
This chapter discusses the early development of knee osteoarthritis with regard to ACL injury. In addition, the kinematic and kinetic changes in the knee after ACL injury are summarized. The interaction between altered joint kinematics and the structural and biological components of articular cartilage is explored as an initiating mechanism of premature cartilage degradation following ACL injury.
Tissue engineering enables the development of functional constructs from cells and has different applications in regenerative medicine and drug screening but also in non-therapeutic approaches.
BACKGROUND: Cartilage tissue engineering is a growing field due to the lack of regenerative capacity of native tissue. The use of bioreactors for cartilage tissue engineering is common, but the results are controversial. Some studies suggest that microgravity bioreactors are ideal for chondrogenesis, while others show that mimicking hydrostatic pressure is crucial for cartilage formation. A parallel study comparing the effects of loading and unloading on chondrogenesis has not been performed.
METHODS: The goal of this study was to evaluate chondrogenesis of human adipose-derived stem cells (hASC) under two different mechanical stimuli relative to static culture: microgravity and cyclic hydrostatic pressure (CHP). Pellets of hASC were cultured for 14 d under simulated microgravity using a rotating wall vessel bioreactor or under CHP (7.5 MPa, 1 Hz, 4 h · d ⁻¹) using a hydrostatic pressure vessel.
RESULTS: We found that CHP increased mRNA expression of Aggrecan, Sox9, and Collagen II, caused a threefold increase in sulfated glycosaminoglycan production, and resulted in stronger vimentin staining intensity and organization relative to microgravity. In addition, Wnt-signaling patterns were altered in a manner that suggests that simulated microgravity decreases chondrogenic differentiation when compared to CHP.
DISCUSSION: Our goal was to compare chondrogenic differentiation of hASC using a microgravity bioreactor and a hydrostatic pressure vessel, two commonly used bioreactors in cartilage tissue engineering. Our results indicate that CHP promotes hASC chondrogenesis and that microgravity may inhibit hASC chondrogenesis. Our findings further suggest that cartilage formation and regeneration might be compromised in space due to the lack of mechanical loading.
Mellor LF, Steward AJ, Nordberg RC, Taylor MA, Loboa EG. Comparison of simulated microgravity and hydrostatic pressure for chondrogenesis of hASC. Aerosp Med Hum Perform. 2017; 88(4):377–384.
Objective:
Low-amplitude, high-frequency whole-body vibration (WBV) has been adopted for the treatment of musculoskeletal diseases including osteoarthritis; however, there is limited knowledge of the direct effects of vibration on joint tissues. Our recent studies revealed striking damage to the knee joint following exposure of mice to WBV. The current study examined the effects of WBV on specific compartments of the murine tibiofemoral joint over 8 weeks, including microarchitecture of the tibia, to understand the mechanisms associated with WBV-induced joint damage.
Design:
Ten-week-old male CD-1 mice were exposed to WBV (45 Hz, 0.3 g peak acceleration; 30 min/day, 5 days/week) for 4 weeks, 8 weeks, or 4 weeks WBV followed by 4 weeks recovery. The knee joint was evaluated histologically for tissue damage. Architecture of the subchondral bone plate, subchondral trabecular bone, primary and secondary spongiosa of the tibia was assessed using micro-CT.
Results:
Meniscal tears and focal articular cartilage damage were induced by WBV; the extent of damage increased between 4 and 8-week exposures to WBV. WBV did not alter the subchondral bone plate, or trabecular bone of the tibial spongiosa; however, a transient increase was detected in the subchondral trabecular bone volume and density.
Conclusions:
The lack of WBV-induced changes in the underlying subchondral bone suggests that damage to the articular cartilage may be secondary to the meniscal injury we detected. Our findings underscore the need for further studies to assess the safety of WBV in the human population to avoid long-term joint damage.
Knorpel ist ein porosUpermeables, viskoelastisches, kollagenreiches Gewebe, dessen funktionelles Verstandnis fur die Entwicklung von kunstlichem Knorpelgewebe so wie von innovativen Therapieansatzen der OA von groser Bedeutung ist. In dieser Arbeit wurde mithilfe einer in vivo Studie die kurzfristige Reaktion des Gelenkknorpels der patellofermoralen und tibiofemoralen Gelenke auf mechanische Belastungen unterschiedlicher Amplitude und Frequenz untersucht. Ziel war, das Deformationsverhalten des Knorpels in Abhangigkeit von der Charakteristik der Belastung zu quantifizieren und die Mechanosensitivitat eines Biomarkers zu studieren sowie den Zusammenhang zwischen Deformation und dem mechanosensitiven Marker zu untersuchen. Eine mechanische Belastung mit niedriger Frequenz und hoher Amplitude (Springen) wurde einer mechanischen Belastung mit hoher Wie derholfrequenz und niedriger Amplitude (Laufen) gegenubergestellt. Die Intervention Springen bestand aus 100 Niedersprungen von einem 73 cm hohen Sprungtisch, die Intervention Laufen aus einem 30 min langen Lauf mit einer Geschwindigkeit von 2,2 m/s. Dieses Untersuchungsdesign gewahrleistete eine annähernd gleich grose mechanische Gesamtbelastung auf das Kniegelenk bei beiden Interventionen. Zur Erstellung eines Lauf- und Sprungprotokolls wurden Vorversuche durchgefuhrt, in denen Bewegungsabläufe beim Laufen und Springen mithilfe von Modellrechnungen analysiert und ausgewertet wurden. Die Parameter, die hierbei zur Vergleichbarkeit herangezogen wurden, waren zum einen die mittlere mechanische Leistung bis 50 ms nach dem ersten Bodenkontakt des Probanden und zum anderen die gesamte kinetische Energie. Das Protokoll wurde so erstellt, dass in beiden Interventionen diese beiden Parameter, und somit die gesamte mechanische Belastung, annahernd gleich gros waren, sodass sich die Belastungen lediglich in Amplitude und Frequenz unterschieden. Die Interventionen wurden untereinander und mit der Kontroll-Intervention Ruhe (30 min langes Sitzen auf einem Stuhl) verglichen. Das festgelegte Untersuchungsprogramm (Ruhe, Laufen und Springen) wurde an drei Versuchstagen mit 14 gesunden jungen untrainierten Probanden durchgeführt. An jedem Versuchstag erfolgten nach einer 30-minütigen Ruhephase vor und nach Intervention eine Blutentnahme und eine Kernspintomographie des Kniegelenkes sowie vier weitere Blutentnahmen nach Interventionsende (30 min, 60 min, 120 min und 180 min). Als etablierter mechanosensitiver Biomarker des Knorpels diente die Serum- Konzentration des Knorpelmatrixproteins COMP (Cartilage oligomeric matrix pro- tein), das vermutlich durch mechanische Belastung vom Knorpel in die Synovialflus- sigkeit und von dort ins Blut gedrangt wird (Kersting et al. U 2005, Mundermann et al. U 2005). Die Veränderungen der ermittelten Serum COMP-Konzentrationen (Lau- fen: +30,7 %, Springen: +32,3 %) und die Dauer dieser Anstiege (je 60 min) fügen sich sehr gut in die in der Literatur beschriebenen Unterschiede von Pra- und Postwerten, also Werten vor und nach Belastungsinterventionen, sowie Anstiegsdauern ein (Liu et al. U 2010, Mundermann et al. U2009). Nach Segmentierung des tibiofemoralen und patellaren Gelenkknorpels wurden diese dreidimensional rekonstruiert und die Knorpeldeformationen (Knorpelvolumen und Knorpeldicke) berechnet und verglichen. Bei der Intervention Ruhe konnten – bis auf den medialen lasttragenden Bereich des Femurs – keine Unterschiede in den Untersuchungsparametern festgestellt werden. Die gefundene Zunahme von Knorpelvolumen und –dicke im medialen Femurbereich lasst sich moglicherweise dadurch erklaren, dass die 30 min lange Ruhepause vor Durchfuhrung des MRT fur diesen Bereich nicht hinreichend lang war, um den Knorpel vollstandig zu entlasten. Die Hohe der in der Regel signifikanten Abnahmen der Knorpelgrosen nach den beiden Belastungen lasst sich ebenfalls gut in die in der Literatur angegebene Knorpeldeformation durch mechanische Belastung einordnen (Boocock et al. U 2009, Kessler et al. U 2006, Eckstein et al. U 2005). Anders als in einer Studie von Eckstein et al. (2005) konnten nach den Interventionen, sowohl im patellaren als auch im tibiofemoralen Knorpel, signifikante Unterschiede festgestellt werden. Die Knorpeldeformation fiel in den untersuchten Knorpelregionen (Ausnahme war die Knorpeldicke des medialen Tibiabereichs) nach Laufbelastung hoher aus als nach Sprungbelastung. Im lateralen Tibiabereich war dieser Unterschied zwischen den beiden Interventionen auch signifikant. Dieser Befund stutzt die Hypothese der Abhangigkeit der Knorpeldeformation von der jeweiligen Belastungscharakteristik: Je hoher die Amplitude und je geringer die Frequenz ist, desto geringer ist die Knorpeldeformation. Ein Erklarungsansatz dieses Ergebnisses liegt in der funktionellen Struktur des Knorpels als viskoelastisches Gewebe. Aufgrund der niedrigen Frequenz konnte sich einerseits die verdrangte Gewebsflüssigkeit wieder rückverteilt haben, andererseits konnte der Knorpel aufgrund der kurzen hohen Amplitude nicht ausreichend Zeit gehabt haben, sich adaquat physiologisch zu deformieren. Eine Differenzierung zwischen diesen beiden Erklarungsmodellen ware mittels unterschiedlicher Reaktionen eines Biomarkers, der bei Knorpelzellzerstorung ansteigt, moglich. Zwar ist COMP prinzipiell ein Kandidat fur solch einen spezifischen mechanosensitiven Knorpelmarker, allerdings fand sich kein signifikanter Unterschied im Verlauf der Serum COMP-Konzentration zwischen den Belastungsinterventionen (ANOVA). Die Mechanosensitivitat des Biomarkers COMP konnte bestatigt werden, allerdings konnte eine negative lineare Korrelation zwischen Veranderungen der Serum COMP-Konzentration und dem gesamten Knorpelvolumen – wie von Kersting et al. (2005) berichtet – nicht festgestellt werden. Es wurde sogar eine signifikante positive lineare Korrelation sowohl der Veranderung des gesamten Knorpelvolumens als auch der gesamten dicke mit der Veranderung der Serum COMP-Konzentration nach der Sprungbelastung gefunden. Diese Korrelation legt nahe, dass durch niedrige Frequenz ein Mechanismus getriggert wird, der zum Beispiel durch erhohte Regeneration des Knorpels und Clearance-Steigerung von COMP-Molekulen aus der Synovialflussigkeit ins Blut zu der beschriebenen positiven Korrelation fuhrt, sodass bei geringer Knorpeldeformation eine hohere Serum COMP-Konzentration zu erwarten ware und umgekehrt. Obwohl der genaue Mechanismus der Erhohung der Serum COMP-Konzentration nach mechanischer Belastung nicht bekannt ist, liesen sich die beschriebenen Beobachtungen durch die mogliche Abgabe von COMP wahrend der Regenerationsphase ins Blut erklaren. Dies ist die erste in vivo Studie zum Vergleich von in Amplitude und Frequenz unterschiedlichen Belastungsstimuli auf den Knorpel, die daruber hinaus eine gleich grose Gesamtbelastung auf das Kniegelenk in den verschiedenen Interventionen ansetzt: Frequenzerhohung der Belastung fuhrt zu einer Zunahme des Deformationsverhaltens des Knorpels, selbst wenn dabei die Amplitude der einzelnen Belastungen abnimmt (bei konstanter gesamter mechanischer Belastung). Als Ursache fur diesen Unterschied werden verschiedene Hypothesen diskutiert. Der Verlauf der Serum COMP-Konzentration nach mechanischer Belastung hat vermutlich einen komplexeren Mechanismus als bislang angenommen und scheint neben mechanischen auch biochemischen Einflussen (z. B. Clearance von COMP-Molekulen aus dem Gelenk) zu unterliegen. Weitere Studien mit einer groseren Personenstichprobe und Probanden unterschiedlichen Alters und Trainingszustandes sind zur abschliesenden Beschreibung des belastungsabhangigen Verhaltens des Gelenkknorpels erforderlich.
Articular cartilage is essential for unconfined function of the musculoskeletal system. The effects of immobilization on hyaline cartilage have been investigated for many decades in cell and animal models, and it is known that normal mechanical loading, as experienced in daily life, is essential for cartilage health. Because of the slow rate of metabolism of cartilage, the time line for intervention experiments needs to be longer than for other skeletal tissues and the regenerative capacity of the cartilage is very limited, once degradation occurs. Thus, performing unloading experiments in healthy humans is difficult. A few studies have been performed in patient cohorts that experienced unloading due to injury, and the results suggest that human cartilage health is negatively affected by unloading.
Space flight research offers a unique opportunity to investigate musculoskeletal tissue adaptation to immobilization in either bed rest or Space flight experiments. Data on cartilage health are sparse but suggest that it is necessary to assess the risk of cartilage deconditioning during extensive human Space travel. Results from this context offer the unique possibility to broaden our understanding of the role of mechanical loading for tissue health.
The in Vivo pathomechanics of osteoarthritis (OA) at the knee is described in a framework that is based on an analysis of studies describing assays of biomarkers, cartilage morphology, and human function (gait analysis). The framework is divided into an Initiation Phase and a Progression Phase. The Initiation Phase is associated with kinematic changes that shift load bearing to infrequently loaded regions of the cartilage that cannot accommodate the loads. The Progression Phase is defined following cartilage breakdown. During the Progression Phase, the disease progresses more rapidly with increased load. While this framework was developed from an analysis of in Vivopathomechanics, it also explains how the convergence of biological, morphological, and neuromuscular changes to the musculoskeletal system during aging or during menopause lead to the increased rate of idiopathic OA with aging. Understanding the in Vivo response of articular cartilage to its physical environment requires an integrated view of the problem that considers functional, anatomical, and biological interactions. The integrated in Vivoframework presented here will be helpful for the interpretation of laboratory experiments as well as for the development of new methods for the evaluation of OA at the knee.
The skeleton's sensitivity to mechanical stimuli represents a critical determinant of bone mass and morphology. We have proposed that the extremely low level (<10 microstrain), high frequency (20-50 Hz) mechanical strains, continually present during even subtle activities such as standing are as important to defining the skeleton as the larger strains typically associated with vigorous activity (>2000 microstrain). If these low-level strains are indeed anabolic, then this sensitivity could serve as the basis for a biomechanically based intervention for osteoporosis. To evaluate this hypothesis, the hindlimbs of adult female sheep were stimulated for 20 minutes/day using a noninvasive 0.3g vertical oscillation sufficient to induce approximately 5 microstrain on the cortex of the tibia. After 1 year of stimulation, the physical properties of 10-mm cubes of trabecular bone from the distal femoral condyle of experimental animals (n = 8) were compared with controls (n = 9), as evaluated using microcomputed tomography (μCT) scanning and materials testing. Bone mineral content (BMC) was 10.6% greater (p < 0.05), and the trabecular number (Tb.N) was 8.3% higher in the experimental animals (p < 0.01), and trabecular spacing decreased by 11.3% (p < 0.01), indicating that bone quantity was increased both by the creation of new trabeculae and the thickening of existing trabeculae. The trabecular bone pattern factor (TBPf) decreased 24.2% (p < 0.03), indicating trabecular morphology adapting from rod shape to plate shape. Significant increases in stiffness and strength were observed in the longitudinal direction (12.1% and 26.7%, respectively; both, p < 0.05), indicating that the adaptation occurred primarily in the plane of weightbearing. These results show that extremely low level mechanical stimuli improve both the quantity and the quality of trabecular bone. That these deformations are several orders of magnitude below those peak strains which arise during vigorous activity indicates that this biomechanically based signal may serve as an effective intervention for osteoporosis.
An Mr = 524,000 oligomeric protein was isolated from bovine cartilage and designated COMP (Cartilage Oligomeric Matrix Protein). The protein is composed of disulfide-bonded subunits with an apparent Mr of 100,000 each. It is markedly anionic, probably due to its high contents of aspartic acid and glutamic acid, as well as to its substitution with negatively charged carbohydrates. COMP was found in all cartilages analyzed, but could not be detected in other tissues by enzyme-linked immunosorbent assay of guanidine HCl extracts. Within a given cartilage, COMP shows a preferential localization to the territorial matrix surrounding the chondrocytes.
The capacity of articular cartilage matrix to recover during 50 weeks of remobilisation after an atrophy caused by 11 weeks of immobilisation of the knee (stifle) joint in 90 degrees flexion starting at the age of 29 weeks, was studied in young beagle dogs.
Proteoglycan concentration (uronic acid) and synthesis ([35S]sulphate incorporation) were determined in six and three knee joint surface locations, respectively. Proteoglycans extracted from the cartilages were characterised by chemical determinations, gel filtration, and western blotting for chondroitin sulphate epitope 3B3.
The proteoglycan concentrations that were reduced in all sample sites immediately after the immobilisation, remained 14-28% lower than controls after 50 weeks of remobilisation in the patella, the summit of medial femoral condyle, and the superior femoropatellar surface. In the contralateral joint, there was a 49% increase of proteoglycans in the inferior femoropatellar surface after remobilisation, while a 34% decrease was simultaneously noticed on the summit of the medial femoral condyle. Total proteoglycan synthesis was not significantly changed after immobilisation or 50 weeks' remobilisation in the treated or contralateral joint, compared with age matched controls. The chondroitin 6- to 4- sulphate ratio was reduced by immobilisation both in the radioactively labelled and the total tissue proteoglycans. In the remobilised joint, this ratio was restored in femur, while in tibia it remained at a level lower than controls. Neither immobilisation nor remobilisation induced epitopes recognised by the monoclonal antibody 3B3 on native (undigested) proteoglycans.
These results show that the depletion of proteoglycans observed after 11 weeks of immobilisation was not completely restored in certain surface sites after 50 weeks of remobilisation. The significant changes that developed in the contralateral joint during the remobilisation period give further support to the idea that a permanent alteration of matrix metabolism results even from a temporary modification of loading pattern in immature joints.
We determined the tissue distribution of cartilage oligomeric matrix protein (COMP) in man and evaluated COMP in synovial fluid (SF) and serum. COMP was purified from human articular cartilage. Polyclonal antibodies were used to detect COMP in tissue cryosections and protein extracts. COMP was determined quantitatively and qualitatively in SF and serum by competitive enzyme-linked immunosorbent assay and immunoblotting. Knee joint SF was taken from nine cadaveric and six living controls, 52 patients with osteoarthritis (OA), 85 patients with rheumatoid arthritis (RA) and 60 patients with other forms of inflammatory arthritis. The degradative potential of SF on native COMP was tested in vitro. The highest concentrations of COMP were measured in articular cartilage and meniscus, the lowest in rib and trachea. Compared with controls, the concentrations of COMP in SF and serum were elevated in 36 and 50% of the patients. A total of 84% of patients with RA and 60% of patients with other forms of inflammatory arthritis showed significant amounts of low-molecular-weight COMP fragments (50-70 kDa) in SF. In contrast, SF fragments were present in only 21% of the OA patients. Furthermore, 13% of SF taken from patients with RA or other forms of inflammatory arthritis were able to degrade COMP in vitro. Using inhibitors, the involvement of serine proteinases could be demonstrated in only 8% of the cases. Based on these results, the absolute levels of COMP in SF and serum, and its fragmentation pattern in SF, seem to be promising as markers of joint tissue metabolism.
Although the skeleton's adaptability to load-bearing has been recognized for over a century, the specific mechanical components responsible for strengthening it have not been identified. Here we show that after mechanically stimulating the hindlimbs of adult sheep on a daily basis for a year with 20-minute bursts of very-low-magnitude, high-frequency vibration, the density of the spongy (trabecular) bone in the proximal femur is significantly increased (by 34.2%) compared to controls. As the strain levels generated by this treatment are three orders of magnitude below those that damage bone tissue, this anabolic, non-invasive stimulus may have potential for treating skeletal conditions such as osteoporosis.
Departing from the premise that it is the large-amplitude signals inherent to intense functional activity that define bone morphology, we propose that it is the far lower magnitude, high-frequency mechanical signals that continually barrage the skeleton during longer term activities such as standing, which regulate skeletal architecture. To examine this hypothesis, we proposed that brief exposure to slight elevations in these endogenous mechanical signals would suffice to increase bone mass in those bones subject to the stimulus. This was tested by exposing the hind limbs of adult female sheep (n = 9) to 20 min/day of low-level (0.3g), high-frequency (30 Hz) mechanical signals, sufficient to induce a peak of approximately 5 microstrain (micro epsilon) in the tibia. Following euthanasia, peripheral quantitative computed tomography (pQCT) was used to segregate the cortical shell from the trabecular envelope of the proximal femur, revealing a 34.2% increase in bone density in the experimental animals as compared with controls (p = 0.01). Histomorphometric examination of the femur supported these density measurements, with bone volume per total volume increasing by 32% (p = 0.04). This density increase was achieved by two separate strategies: trabecular spacing decreased by 36.1% (p = 0.02), whereas trabecular number increased by 45.6% (p = 0.01), indicating the formation of cancellous bone de novo. There were no significant differences in the radii of animals subject to the stimulus, indicating that the adaptive response was local rather than systemic. The anabolic potential of the signal was evident only in trabecular bone, and there were no differences, as measured by any assay, in the cortical bone. These data suggest that subtle mechanical signals generated during predominant activities such as posture may be potent determinants of skeletal morphology. Given that these strain levels are three orders of magnitude below strains that can damage bone tissue, we believe that a noninvasive stimulus based on this sensitivity has potential for treating skeletal complications such as osteoporosis.
The cartilage oligomeric matrix protein (COMP) and matrilins are abundant non-collagenous proteins in the cartilage extracellular matrix. In the presence of calcium, COMP and matrilin-1 elute together in the gel filtration of cartilage extracts and can be co-immunoprecipitated. In a screen for ligands of matrilin-1, -3, and -4 using an ELISA-style binding assay, COMP was identified as a prominent binding partner for all three, indicating a conservation of the COMP interaction among matrilins. The interaction of COMP and matrilin-4 is saturable, and an apparent K(D) of 1 nm was determined. However, only the full-length COMP and the full-length matrilin-4 proteins showed a strong interaction, indicating that the oligomeric structures markedly increase the affinity. Mutations in COMP or matrilin-3 cause related forms of human chondrodysplasia, and the COMP mutation D469Delta, which is found in patients with pseudoachondroplasia, has been shown to cause a reduced calcium binding. Despite this, the mutation causes only a slight decrease in matrilin-4 binding. This indicates that impaired binding of COMP to matrilins does not cause the pseudoachondroplasia phenotype but rather that matrilins may be coretained in the rough endoplasmatic reticulum where COMP accumulates in the chondrocytes of patients.
The effects of vibration on the human body have been documented for many years. Recently, the use of vibration for improving the training regimes of athletes has been investigated. Vibration has been used during strength-training movements such as elbow flexion, and vibration has also been applied to the entire body by having subjects stand on vibration platforms. Exposure to whole-body vibration has also resulted in a significant improvement in power output in the postvibratory period and has been demonstrated to induce significant changes in the resting hormonal profiles of men. In addition to the potential training effects of vibration, the improvement in power output that is observed in the postvibratory period may also lead to better warm-up protocols for athletes competing in sporting events that require high amounts of power output. These observations provide the possibility of new and improved methods of augmenting the training and performance of athletes through the use vibration training. Despite the potential benefits of vibration training, there is substantial evidence regarding the negative effects of vibration on the human body. In conclusion, the potential of vibration treatment to enhance the training regimes of athletes appears quite promising. It is essential though that a thorough understanding of the implications of this type of treatment be acquired prior to its use in athletic situations. Future research should be done with the aim of understanding the biological effects of vibration on muscle performance and also the effects of different vibration protocols on muscle performance.
Whole body vibration has been recently proposed as an exercise intervention because of its potential for increasing force generating capacity in the lower limbs. Its recent popularity is due to the combined effects on the neuromuscular and neuroendocrine systems. Preliminary results seem to recommend vibration exercise as a therapeutic approach for sarcopenia and possibly osteoporosis. This review analyses state of the art whole body vibration exercise techniques, suggesting reasons why vibration may be an effective stimulus for human muscles and providing the rationale for future studies.
Vibration transmitted to the whole body or part of it has been extensively studied in relation to the risks to the health and safety of workers. These studies have highlighted the particular danger of lower-back morbidity and spinal trauma arising after prolonged exposure to vibration. However, short-term exposure to whole-body vibration (WBV) or the use of vibrating dumbbells can have beneficial effects on the musculoskeletal system. As a consequence of this encouraging work, many manufacturers have developed exercise devices characterized by vibrating plates transmitting vibration to the whole body and vibrating dumbbells. Preliminary results seem to recommend WBV exercise as a therapeutic alternative for preventing/reversing sarcopenia and possibly osteoporosis. However, there is a paucity of well designed studies in the elderly. In particular, there is a lack of understanding of the physiological mechanisms involved in the adaptive responses to vibration exposure, and of the most appropriate vibration parameters to be used in order to maximize gains and improve safety. The effectiveness of this novel exercise modality on musculoskeletal structures is examined in this review. The physiological mechanisms involved in the adaptive responses to vibration exercise are discussed and suggestions for future studies are made.
IntroductionCategories of vibrationResponse to vibration loadStrength and power developmentDiscussionReferences
The aim of this study was to test the hypothesis that a change in serum cartilage oligomeric matrix protein (COMP) concentration is related to joint load during a 30-min walking exercise in patients with medial compartment knee osteoarthritis (OA) and in age-matched control subjects. Blood samples were drawn from 42 patients with medial compartment knee OA and from 41 healthy age-matched control subjects immediately before, immediately after, and 0.5, 1.5, 3.5, and 5.5 h after a 30-min walking exercise on a level outdoor walking track at self-selected normal speed. Serum COMP concentrations were determined using a commercial ELISA. Basic time-distance gait variables were recorded using an activity monitor. Joint loads were measured using gait analysis. Serum COMP concentrations increased immediately after the walking exercise (+6.3% and +5.6%; p < 0.001) and decreased over 5.5 h after the exercise (-11.1% and -14.6%; p < 0.040 and p = 0.001) in patients and control subjects, respectively. The magnitude of increase in COMP concentration did not differ between groups (p = 0.902) and did not correlate with any variables describing ambulatory loads at the joints of the lower extremity. These results, taken together with a previous study of a younger healthy population, suggest the possibility that the influence of ambulatory loads on cartilage turnover is dependent on age.
To investigate changes in the knee during the first year after acute rupture of the anterior cruciate ligament (ACL) of volumes of joint fluid (JF), bone marrow lesions (BMLs), and cartilage volume (VC), and cartilage thickness (ThCcAB) and cartilage surface area (AC). To identify factors associated with these changes.
Fifty-eight subjects (mean age 26 years, 16 women) with an ACL rupture to a previously un-injured knee were followed prospectively using a 1.5T MR imager at baseline (within 5 weeks from injury), 3 months, 6 months, and 1 year. Thirty-four subjects were treated with ACL reconstruction followed by a structured rehabilitation program and 24 subjects were treated with structured rehabilitation only. Morphometric data were acquired from computer-assisted segmentation of MR images. Morphometric cartilage change was reported as mean change divided by the standard deviation of change (standard response mean, SRM).
JF and BML volumes gradually decreased over the first year, although BML persisted in 62% of the knees after 1 year. One year after the ACL injury, a reduction of VC, AC and ThCcAB (SRM -0.440 or greater) was found in the trochlea femur (TrF), while an increase of VC and ThCcAB was found in the central medial femur (cMF) (SRM greater than 0.477). ACL reconstruction was directly and significantly related to increased JF volume at 3 and 6 months (P<0.001), BML volume at 6 months (P=0.031), VC and ThCcAB in cMF (P<0.002) and decreased cartilage area in TrF (P=0.010) at 12 months.
Following an acute ACL tear, cMF and TrF showed the greatest consistent changes of cartilage morphometry. An ACL reconstruction performed within a mean of 6 weeks from injury was associated with increased ThCcAB and VC in cMF and decreased AC in TrF, compared to knees treated without reconstruction. This may suggest a delayed structural restitution in ACL reconstructed knees.
Physiological effects seen in eight test subjects during a 5-d bedrest experiment in the head-down position (0,-4,-8,-12degrees) were studied. It was shown that the antiorthostatic hypokinesia at -12degrees could reproduce physiological responses shown by space crewmembers more closely than recumbent bedrest. Our observations help to stimulate an acute stage of human adaptation to the weightless state and to assess the part played by gravity-induced blood redistribution in the development of physiological changes.
ARTICULAR cartilage contains a high concentration of acid
glycosaminoglycans (GAG), reaching 6% by wet weight and associated with
fixed charge densities up to 0.2 mEq g-1. This leads to
considerable swelling pressure within cartilage, due to, first, the
strongly non-ideal osmotic pressure, characteristic of polymer
solutions, which increases sharply with concentration and, second, the
ionic contribution, in accordance with the Gibbs-Donnan equilibrium.
Ogston and Wells1-3 have estimated the values of these two
components and I have calculated them from my experimental data on
cartilage4,5. The two components of swelling pressure are
approximately of the same order of magnitude and can reach values as
high as 1.7kgcm-2 (refs 4 and 5). Since normal cartilage does
not swell in solution, even when it is removed from the joint and cut
into thin (250 µm) slices (lowest curve, Fig. 1), this implies
that its high swelling pressure must be counteracted by considerable
elastic forces within the collagen fibre network. It has been known for
some time that the concentration of GAG gradually increases from the
articular surface to the deep zone (for example, refs 6 and 7). A
typical variation of total GAG content with depth, measured as fixed
charge density, is shown in Table 1. I now suggest that this particular
profile is adapted to the physiological function and mechanical
properties of cartilage.
Two cartilage specific macromolecules, cartilage oligomeric matrix protein (COMP) and proteoglycan, were quantified by immunoassay
in sera of two groups of patients with rheumatoid arthritis (RA) of recent onset to evaluate the prognostic value of such
measurements. Patients with rapidly progressive joint destruction had increased COMP concentrations initially, which subsequently
decreased. A group with more benign disease, and less extensive joint damage, had normal COMP levels throughout the study
period. Serum concentrations of proteoglycan were normal in both groups. Thus measurement of COMP in serum early in the course
of RA holds promise as a prognostic marker for development of joint destruction in this disease
Knees of mature dogs were immobilized for 6 weeks by long-leg casts allowing 8 degrees-15 degrees of motion, a model studied by others, or with external fixators, a new, more severe model that kept the joints rigid. Some animals were allowed to recover for 1 week after the immobilization period. Articular cartilage was examined histologically and biochemically. After 6 weeks of immobilization, water increased 7% in both casted and fixator-immobilized joints compared with normal knee cartilage, while hexuronic acid was 23 and 28% lower, respectively. The limited motion permitted by the casts resulted in a smaller depression of proteoglycan synthesis and less proteoglycan loss during immobilization than occurred in the rigid external fixator group. The protective effect of limited motion was shown clearly during the recovery period: as measured by hexuronic acid content, cartilage from the casted joints had almost recovered within 1 week, whereas the external fixator group experienced little or no recovery during the week after treatment. In contrast to previous studies by others with casted joints, both newly synthesized [35S]sulfate-labeled and accumulated unlabeled proteoglycans from both casted and fixator-immobilized cartilages were able to form complexes with exogenous hyaluronic acid to the same extent as those from control cartilage. Thus, in immobilized cartilage, failure of the newly synthesized proteoglycan to bind to hyaluronate is not a mechanism of accelerated proteoglycan loss. The accelerated proteoglycan turnover appears to be caused by a combination of decreased synthesis and increased proteolysis of the secreted proteoglycans.(ABSTRACT TRUNCATED AT 250 WORDS)