Article

Efficacy of oral administration of yoghurt supplemented with a preparation containing hyaluronic acid (Mobilee™) in adults with mild joint discomfort: A randomized, double-blind, placebo-controlled intervention study

Authors:
  • University of Barcelona. Instituto Poal Reumatologia
  • ADreamUP Innovation & creativity
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Abstract

A prospective, randomized, double-blind, placebo-controlled study was designed with 40 healthy individuals with joint discomfort. The effect of oral supplementation with a natural product containing hyaluronic acid included in a yoghurt matrix was evaluated in terms of functional and quality-of-life parameters. An isokinetic dynamometer was used to measure maximum muscle strength, total work and mean power. Participants were divided into 2 groups (n = 20) and ate yoghurt that was either supplemented or not supplemented with the hyaluronic acid product daily for a period of 90 days. The increase in the maximum peak torque of the knee extensors compared to baseline values was 7.6 ± 7.6 Nm for the supplemented yoghurt group and 2.5 ± 4.7 Nm for the control group at 180°/s (P = 0.0582), and 6.5 ± 5.8 Nm for the supplemented yoghurt group and −1.0 ± 7.1 Nm for the control group at 240°/s (P < 0.05). The same pattern of response was observed in total work and in mean power (P < 0.05). Differences were less pronounced in the knee flexors. No differences were detected in the Lequesne score and SF-36 survey except for the social functioning subscale at 1 month follow-up. This prospective placebo-controlled nutritional study confirmed that 3 months of oral administration of a natural product containing HA (Mobilee™) in healthy individuals with joint discomfort of the knee provides improvements in muscle strength.

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... The glycosaminoglycan (GAG) hyaluronic acid (HA) is used in the therapeutics of OA, mostly following intraarticular injection (Dougados et al. 1993;Altman and Moskowitz 1998). Recently, however, beneficial effect of HA following oral administration has been also demonstrated (Tashiro et al. 2012;Martinez-Puig et al. 2013). In fact, there is evidence that high-molecular-weight HA is absorbed and distributed to connective tissues after its oral administration (Balogh et al. 2008). ...
... In addition, oral supplementation with HA (as Mobilee TM formulation) reduced the degree of synovial effusion and increased the concentration of HA in synovial fluid in horses diagnosed with osteochondritis (Martínez-Puig et al. 2007). Moreover, a placebo-controlled nutritional study confirmed in humans that 3-month oral administration of HA (as Mobilee TM ) provides improvement in knee muscle strength in individuals with mild joint discomfort (Martinez-Puig et al. 2013). ...
... The supplemented group ate one yoghurt containing Mobilee TM -a rooster comb extract, containing HA (65 %), polysaccharides, and collagen-per day for 90 days. Similar to the outcome of a previous study with another set of volunteers (Martinez-Puig et al. 2013), the daily supplementation with Mobilee TM significantly reduced pain intensity (one of the primary symptoms of joint discomfort) and the degree of synovial effusion (a clinical finding linked to inflammation) and improved the muscular strength parameters compared to placebo. Here, we were particularly interested in novel and accessible biomarkers of articular health improvement related to Mobilee TM intake. ...
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The aim of the study was to explore peripheral blood gene expression as a source of biomarkers of joint health improvement related to glycosaminoglycan (GAG) intake in humans. Healthy individuals with joint discomfort were enrolled in a randomized, double-blind, placebo-controlled intervention study in humans. Subjects ate control yoghurt or yoghurt supplemented with a recently authorized novel food in Europe containing hyaluronic acid (65 %) from rooster comb (Mobilee™ as commercial name) for 90 days. Effects on functional quality-of-life parameters related to joint health were assessed. Whole-genome microarray analysis of peripheral blood samples from a subset of 20 subjects (10 placebo and 10 supplemented) collected pre- and post-intervention was performed. Mobilee™ supplementation reduced articular pain intensity and synovial effusion and improved knee muscular strength indicators as compared to placebo. About 157 coding genes were differentially expressed in blood cells between supplemented and placebo groups post-intervention, but not pre-intervention (p < 0.05; fold change ≥1.2). Among them, a reduced gene expression of glucuronidase-beta (GUSB), matrix metallopeptidase 23B (MMP23B), xylosyltransferase II (XYLT2), and heparan sulfate 6-O-sulfotransferase 1 (HS6ST1) was found in the supplemented group. Correlation analysis indicated a direct relationship between blood cell gene expression of MMP23B, involved in the breakdown of the extracellular matrix, and pain intensity, and an inverse relationship between blood cell gene expression of HS6ST1, responsible for 6-O-sulfation of heparan sulfate, and indicators of knee muscular strength. Expression levels of specific genes in blood cells, in particular genes related to GAG metabolism and extracellular matrix dynamics, are potential biomarkers of beneficial effects on articular health.
... From this list, 4 articles were excluded because no full text was available, also after contacting the main authors, and one article was ex- cluded because it was not reporting clinical data. In the end we selected the following 15 relevant reports (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). These clinical studies can be subdivided ac- cording to the company producing the oral HA treat- ments as in Table 1. ...
... Oralvisc (21) indicated no evident improvement in WOMAC scores, but some in SF-36v2 scores. Interestingly 4 studies with Mobilee (13,(18)(19)(20) (Figure 4). Of the three trials testing the isokinetic dynamometer, two found significant increase in mus- cular strength at isokinetic peak torque at 240º (18,19) ( Figure 5) and one also at 180º (20), but only in men. ...
... Interestingly 4 studies with Mobilee (13,(18)(19)(20) (Figure 4). Of the three trials testing the isokinetic dynamometer, two found significant increase in mus- cular strength at isokinetic peak torque at 240º (18,19) ( Figure 5) and one also at 180º (20), but only in men. ...
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Study Objectives: Osteoarthritis (OA) is the most common chronic condition of the joints, affecting approximately 27 million of people in the US and its prevalence is predicted to grow. Recently, symptomatic slowacting drugs for osteoarthritis (SYSADOA) have been vastly studied and have generated considerable interest among clinicians and the public. In particular, the use of oral hyaluronic acid (HA) treatments for knee pain has been the source of much research and it is now widely adopted in the clinic for its safety and relative low cost. The aim of this study is to discuss the efficacy of oral HA in treating knee OA based on the most recent data from the literature as well as to encourage the use of objective measures to determine more effectively the efficacy of current therapies for knee OA. Methods: We searched the PubMed database up to 23/01/2018 based on data from randomized, double-blind, placebo-controlled trials, non-controlled trials and cohort studies conducted in adult subjects. The search words used contained the terms: oral hyaluronan (HA) and knee osteoarthritis (OA). We selected 15 relevant reports. The review was registered on PROSPERO (International prospective register of systematic reviews), registration number CRD42018104127. Results: Companies in Japan, US and Europe produced different oral supplements containing HA in various formulations, which have been tested in clinical trials. The vast majority of the studies analyzed found significant improvements of scores including VAS, WOMAC, JKOM and SF-36v2 in patients with moderate knee OA after short (1-4 months) daily treatments with oral HA preparations , compared to placebo-treated controls. Interestingly, few studies proposed the use of objective measures to evaluate the efficacy of HA treatments with ultrasonography and an isokinetic dynamometer, but they obtained modest and controversial results. Conclusions: Current clinical data on oral HA products for the treatment of mild to moderate knee OA are promising and in line with The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) recommendation to use SYSADOA. However, more high-quality research with larger sample sizes and longer exposures to the oral treatment is needed to confirm these data. Particularly, more effort is required to standardize the treatments (final dose of HA, molecular weight of HA and presence of other active molecules) and to assess the results on patients with objective measures.
... The glycosaminoglycan (GAG) hyaluronic acid (HA) is used in the therapeutics of OA, mostly following intraarticular injection (Dougados et al. 1993;Altman and Moskowitz 1998). Recently, however, beneficial effect of HA following oral administration has been also demonstrated (Tashiro et al. 2012;Martinez-Puig et al. 2013). In fact, there is evidence that high-molecular-weight HA is absorbed and distributed to connective tissues after its oral administration (Balogh et al. 2008). ...
... In addition, oral supplementation with HA (as Mobilee TM formulation) reduced the degree of synovial effusion and increased the concentration of HA in synovial fluid in horses diagnosed with osteochondritis (Martínez-Puig et al. 2007). Moreover, a placebo-controlled nutritional study confirmed in humans that 3-month oral administration of HA (as Mobilee TM ) provides improvement in knee muscle strength in individuals with mild joint discomfort (Martinez-Puig et al. 2013). ...
... The supplemented group ate one yoghurt containing Mobilee TM -a rooster comb extract, containing HA (65 %), polysaccharides, and collagen-per day for 90 days. Similar to the outcome of a previous study with another set of volunteers (Martinez-Puig et al. 2013), the daily supplementation with Mobilee TM significantly reduced pain intensity (one of the primary symptoms of joint discomfort) and the degree of synovial effusion (a clinical finding linked to inflammation) and improved the muscular strength parameters compared to placebo. Here, we were particularly interested in novel and accessible biomarkers of articular health improvement related to Mobilee TM intake. ...
... In human beings, HA is present in every connective tissue and organ such as skin, synovial fluid, blood vessels, serum, brain, cartilage, heart valves, and the umbilical cord[7]. In particular, synovial fluid has the highest concentration of HA anywhere in the body at 3–4 mg/mL[8].Significant improve of joint mechanics and muscle function[42]Meta-analysis included in two randomized, controlled, doubleblind, placebo-controlled trials HA mixture at 80 mg (HA 48 mg; MW N/ A) daily for 3 months 148 healthy individuals with mild knee pain (in Spain) ...
... The search words used for all databases contained the terms; hyaluronan, intake and knee pain. We selected following 13 relevant reports after full text review[31][32][33][34][35][36][37][38][39][40][41][42][43]. Many randomized, double-blind, placebo-controlled trials have demonstrated the effectiveness of dietary HA in alleviating knee pain since 2008 in the US, EU, and Asia (Table 1). ...
... Thus, HA intake and quadriceps-strengthening exercise affectively alleviate knee pain particularly in patients aged ≤70 years (Fig. 3). In 2013, Martinez-Puig et al.[42]reported that 50 healthy subjects with joint discomfort (VAS between 10 and 40 mm; HA group, n = 20; placebo group, n = 20, mean age, 59.6) were administered an HA mixture at 80 mg/day (HA content, 48 mg/day) or placebo for 90 days and outcomes were evaluated using an isokinetic dynamometer. Maximum peak torque was significantly greater in the HA group than in the placebo group (p < 0.05). ...
Article
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Hyaluronan (HA) is a component that is particularly abundant in the synovial fluid. Randomized, double-blinded, placebo-controlled trials carried out between 2008 and 2015 have proven the effectiveness of HA for the treatment of symptoms associated with synovitis, and particularly, knee pain, relief of synovial effusion or inflammation, and improvement of muscular knee strength. The mechanism by which HA exerts its effects in the living body, specifically receptor binding in the intestinal epithelia, has gradually been clarified. This review examines the effects of HA upon knee pain as assessed in clinical trials, as well as the mechanism of these effects and the safety of HA.
... Twenty-two studies assessed other outcomes: Parkinson's disease risk (3 studies) (Chen et al., 2007;Miyake et al., 2011;Kyrozis et al., 2013), all-cause mortality (3 studies) (Bonthuis et al., 2010;Goldbohm et al., 2011;Soedamah-Muthu et al., 2012), skin complaints (3 studies) (Uenishi et al., 2004Kim et al., 2010), respiratory complaints (3 studies) (Miyake et al., 2010(Miyake et al., , 2012Maslova et al., 2012), joint pain/function (2 studies) (Martinez-Puig et al., 2013;Morina et al., 2013). The remaining 8 studies assessed a variety of other health outcomes: benign breast disease risk (Berkey et al., 2013), estrogen metabolism (Campbell et al., 1999), general mental/ psychological health (Crichton et al., 2010), minor health complaints (Hyland and Sodergren, 1998), immune function (Makino et al., 2010), general health (Mossavar-Rahmani et al., 2002), age of menarche (Ramezani Tehrani et al., 2013), and allergic symptoms (Trapp et al., 1993). ...
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Background: The health effects of conventional yogurt have been investigated for over a century; however, few systematic reviews have been conducted to assess the extent of the health benefits of yogurt. Objective: The aim of this scoping review was to assess the volume of available evidence on the health effects of conventional yogurt. Methods: The review was guided by a protocol agreed a priori and informed by an extensive literature search conducted in November 2013. Randomized controlled trials were selected and categorized according to the eligibility criteria established in the protocol. Results: 213 studies were identified as relevant to the scoping question. The number of eligible studies identified for each outcome were: bone health (14 studies), weight management and nutrition related health outcomes (81 studies), metabolic health (6 studies); cardiovascular health (57 studies); gastrointestinal health (24 studies); cancer (39 studies); diabetes (13 studies), Parkinson's disease risk (3 studies), all-cause mortality (3 studies), skin complaints (3 studies), respiratory complaints (3 studies), joint pain/function (2 studies); the remaining 8 studies reported a variety of other outcomes. For studies of a similar design and which assessed the same outcomes in similar population groups, we report the potential for the combining of data across studies in systematic reviews. Conclusions: This scoping review has revealed the extensive evidence base for many outcomes which could be the focus of systematic reviews exploring the health effects of conventional yogurt consumption.
... Nutraceuticals are suggested to have a role in decreasing pain, improving function and reducing joint progression in OA [12]. Results from randomized controlled studies reported an improvement of pain relief, quality of life and muscle strength in patients with knee OA and mild joint discomfort treated with dietary supplementation of mobilee and MSM [14,[29][30][31]. Furthermore, intake of MSM for 13 weeks decreased degeneration of cartilage at the joint surface in the knee joints of STR/Ort OA mouse model in a dose dependent manner [11]. ...
... Hyaluronic acid -a polymer of N-acetyl-glucosamine and glucuronic acid disaccharide units -is a main and functionally very relevant component of cartilage and synovial fluid. Amelioration of joint dysfunction symptoms following not only intra-articular injection but also oral intake of hyaluronic acid or hyaluronic acidrich mixtures/extracts has been described in affected humans (Martinez-Puig, Möller, Fernández, & Chetrit, 2013;Nelson et al., 2013Nelson et al., , 2015Sanchez et al., 2014;Sola et al., 2015;Tashiro et al., 2012). ...
... Hyaluronic acid -a polymer of N-acetyl-glucosamine and glucuronic acid disaccharide units -is a main and functionally very relevant component of cartilage and synovial fluid. Amelioration of joint dysfunction symptoms following not only intra-articular injection but also oral intake of hyaluronic acid or hyaluronic acidrich mixtures/extracts has been described in affected humans (Martinez-Puig, Möller, Fernández, & Chetrit, 2013;Nelson et al., 2013Nelson et al., , 2015Sanchez et al., 2014;Sola et al., 2015;Tashiro et al., 2012). ...
Article
Background Obesity and osteoarthritis are two multifactorial pathologies that are becoming major medical issues with the aging of the world population and which often appear together. The relationship of osteoarthritis with obesity is complex, involving metabolic and developmental links with inflammatory status in different tissues. Nutritional and pharmacological factors capable of simultaneously targeting the two conditions are of interest. Objectives Our initial studies revealed interesting effects of a glycosaminoglycan (GAG) mixture on adipose cells differentiated in culture. Here, we aimed at testing in an animal study the potential of a commercial preparation rich in that particular GAG mixture and used in osteoarthritis management (Oralvisc™, Bioiberica S.A., Palafolls, Spain) as a co-adjuvant in weight loss strategies. Methods 25-week-old C57BL6/J male mice made obese through high fat-diet feeding displaying a 22% excess body weight relative to controls at the start of the experiment were used. On day 0, the mice were switched to a normal-fat diet and distributed into two groups that received the vehicle (water, control group) or the GAG-rich preparation (treatment group), at a dose of 3 mg/mouse/day (n=7-8 animals/group) daily, by oral route. Body weight, body composition (using a non-invasive magnetic resonance system), and food intake were regularly monitored. The animals were sacrificed on day 32, and blood and tissues were collected. Q-PCR was used to measure the expression of selected genes in gonadal white adipose tissue (gWAT) and brown adipose tissue (BAT), as well as mitochondrial DNA content in gWAT. Results Animals treated with the GAG-enriched preparation tended to lose more body weight and faster than those in the control group, and showed a higher and faster loss of body fat after switching to the normal-fat diet. At sacrifice, adiposity index was 30% lower and circulating leptin levels (which reflect body fat content) 40% lower in the animals treated with the GAG-enriched preparation, which also displayed reduced leptin gene expression in gWAT. Treated animals also showed signs of increased insulin sensitivity, with equal glucemia but lower insulinemia compared with controls. No differences between the two groups were found concerning cumulative energy intake during the 32 days experimental period and Ucp1 and Ppargc1a expression in BAT. However, gene expression of various thermogenic and oxidative metabolism-related genes (Ppara, Cpt1b, Cox5a, Ucp1) were higher in gWAT of treated animals, in which mitochondrial DNA content was also found elevated. Conclusions The results suggest that the GAG rich preparation tested might be useful as a co-adjuvant in weight loss strategies, and may favor mitochondrial activity in WAT. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5581
... While the integrity of polymeric HA structures regulates tissue homeostasis, the decrease of its endogenous production or cleavage of its chains is linked with various diseases related mainly to age. Nowadays, the HA from fermentation (bio-HA) is widely used to restore the endogenous HA properties that have been lost [8,9]. ...
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Oral hyaluronic acid (HA) is a ubiquitous biopolymer that has gained attention as a treatment for local or systemic diseases. Here, we prepared and characterized structures of free HA (f-HA) with a high (>10 5 Da), intermediate (≤10 5 Da), and low (≤10 4 Da) average molar mass (MM); nanoparticles crosslinked with adipic dihydrazide (n-HA); and mixed formulations (mixed-HA) containing f-HA and n-HA. MM distribution determined the structure, hydrodynamic diameter, and zeta potential of the f-HAs. Crosslinking changed the physicochemical properties in n-HA. In vitro tack adhesion assays, using mucin tablets or a viable rat intestinal mucosa, showed better mucoadhesion with f-HA (intermediate MM) and mixed-HA (25% n-HA), especially in the jejunum segment. High MM f-HA presented negligible mucoadhesion. n-HA showed the deepest diffusion into the porous of the membranes. In vivo results showed that, except for high MM f-HA, there is an inverse relationship between rheological changes in the intestinal membrane macerates resulting from mucoadhesion and the effective intestinal permeability that led to blood clearance of the structures. We conclude that the n-HA formulations are promising for targeting other tissues, while formulations of f-HA (intermediate MM) and mixed-HA are better for treating dysbiosis.
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Various cell lines of human synovial fibroblasts derived from synovium obtained at the time of biopsy or total joint-replacement surgery have been established. The synthesis of 3H-labelled hyaluronic acid (HA) in these cells has been determined, and the effects of adding HA of varying molecular size to the cultured cells examined. The results obtained clearly show that the in vitro synthesis of HA by these cells is influenced by the concentration and molecular weight (MW) of the HA in their extracellular environment. Synovial fibroblasts derived from an osteoarthritic joint demonstrated the most marked response on exposure to exogenous HA, showing a stimulation of HA synthesis with preparations of weight-average molecular weight (Mw) greater than 5 X 10(5) in a concentration dependent manner. HA preparations with Mw less than 5 X 10(5) showed little or no effect except at high concentrations where a suppression of biosynthesis was observed. A model to explain these findings is proposed.
Article
The present study uses data from a national, community-based survey to compare the social impact of and medical care use due to 4 musculoskeletal conditions: rheumatoid arthritis, osteoarthritis, lower back pain, and tendinitis. The study also compares the impacts experienced by persons with these conditions with those experienced by a sample of persons having a broader range of musculoskeletal conditions, and by an age-adjusted sample representing the entire U.S. population. Rheumatoid arthritis leads to the most frequent use of physician services; lower back pain results in the most hospitalizations and surgery. Rheumatoid arthritis also causes the most restriction in activity. We found that as a broad group, persons with musculoskeletal disease experience about the same amount of restriction in activity and use about the same amount of medical care as U.S. citizens as a whole. This study demonstrates that health planning on the basis of specific musculoskeletal conditions is necessary to serve the disparate needs of persons with particular, discrete conditions.
Article
Osteoarthritis (OA) is a chronic degenerative disorder characterized by cartilage loss. Its prevalence is high, and it is a major cause of disability. The cause of OA is not known; however, current evidence indicates that it is multifactorial. Major risk factors for osteoarthritis are age, female sex, obesity, geographic factors, occupational knee-bending, physical labour, genetic factors and race, joint trauma, vitamin D deficiency, and chondrocalcinosis. Osteoarthritis causes joint pain, stiffness, and limitation of joint function. Knee involvement is the commonest presentation of this disease all over the world. Given the absence of a curative treatment, it is important to treat osteoarthritis as effectively as possible using a multidisciplinary approach tailored to the patient's needs. This article reviews current thinking on the epidemiology, clinical presentation, lifestyle, genetic epidemiology, and management of osteoarthritis in developing countries.
Article
In contrast with newly isolated cells or early primary cultures, synovial cell lines in standardised growth conditions assume a rather uniform fibroblast-like appearance. However, 2 distinct variations in the cytological pattern can be induced at this stage. The first is characterised primarily by increased numbers of small phase-dense organelles that show the distinctive fluorescence of lysosomes after supravital staining, and are interspersed with vacuoles. The associated functional changes include increased enzyme activity and decreased net synthesis of hyaluronic acid. This variation can be induced by exposure to indigestible neutral sugars, adenosine, or its 5' nucleotides. The second variation consists of a striking reorganisation of cytoplasm by condensation into dense ridges or a dendritic network of processes. It is accompanied by increased hyaluronic acid secretion and is induced by agents that enhance intracellular activity of cyclic adenosine monophosphate, such as dibutyryl cyclic adenosine monophosphate and cholera enterotoxin. It appears possible to direct differentiation in synovial cell lines to correspond at least in part with the presumed functions of the different cell types in the parent tissue. The 2 patterns may be useful markers to correlate with other aspects of synovial cell function in vitro.
Article
This study evaluated at two different test sessions the normality and variability of the isokinetic peak torque (PT), peak work (PW), peak power (PP) and peak torque acceleration energy (PTAE) data outputs in healthy adult males (n = 10) and females (n = 10). The hamstring and quadriceps muscles were tested at the angular velocities of 60 deg/s (a slow speed test) and 240 deg/s (a high speed test). The predictability of the PW, PP and PTAE from the PT was also assessed. The results showed that the consistency of the PW and PP measurements were equal with that of the PT. This was due to equal (almost normal) data distribution, equal variability of the outputs (the coefficient of variation (cv) ranged from 14 to 29% in the PWs and PPs versus 16 to 29% in the PTs), and excellent predictability of the PW and PP from the PT (PTs accounted on an average 85% for the variation seen in the PWs and PPs). In addition, in the regression analyses the standard errors of the estimates (SEEs) were low (less than 10%) and the residuals were distributed nonsystematically. In the PTAE measurements, the results were much more inconsistent, especially during the slow speed of the dynamometer. Compared with PT, PW and PP, the PTAE data distribution differed more frequently from normal distribution and the PTAE outputs showed higher variability. In addition, the PTAE outputs could not be acceptably predicted from the PT. In conclusion, the isokinetic PW and PP measurements can be recommended for clinical use, while the PTAE measurements should not be used routinely.
Article
The putative role and mechanism of action of cytokines in the progression of arthritic diseases such as osteoarthritis (OA) has received particular attention because of the important interaction between articular cartilage and synovium in the pathophysiology of the diseased state. Maintaining matrix homeostasis in the normal adult cartilage phenotype requires normal turnover of matrix components, principally collagen and proteoglycan. Chondrocytes and synovial fibroblasts are targeted, via specific cell-surface receptors, by cytokines like interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) to produce matrix proteases and to suppress the synthesis of collagen and proteoglycan. Thus, cytokines not only favor tissue destruction, but also inhibit tissue repair. A structurally heterogeneous group of factors capable of directly antagonizing cytokine action is described, which acts either by blocking cytokine-receptor binding, inhibiting local cytokine synthesis, or complexing the cytokine into an inactive form. Furthermore, many growth factors, such as transforming growth factor-beta (TGF-beta), can counteract the net effect of cytokines by stimulating the synthesis of matrix components or natural inhibitors of cartilage degrading enzymes.
Article
We have previously reported that naturally occurring sulfated glycosaminoglycans having a chondroitin-type structure and glycosaminoglycan polysulfate (GAGPS, a persulfated derivative of chondroitin sulfate) caused a specific stimulation of hyaluronic acid synthesis in rabbit knee synovial membranes [H. Nishikawa et al. (1985) Arch. Biochem. Biophys. 240, 146-153]. In the present study, the interaction of [3H]GAGPS and the surface of the rabbit knee synovial membranes and the relationship between this interaction and the stimulatory effect of GAGPS on the hyaluronic acid synthesis were examined in order to define the stimulatory mechanism of hyaluronic acid synthesis by GAGPS. A part of the [3H]GAGPS taken up by the synovial membranes was released from the membranes by trypsin treatment. The interaction of [3H]GAGPS and the surface of the isolated synovial membranes was diminished by pretreatment of the membranes with proteases or chelating reagents. Pretreatment of synovial membranes with trypsin or ethylene glycol bis(beta-aminoethyl ether) N,N'-tetraacetic acid had little effect on the basal hyaluronic acid synthesis but caused the loss of GAGPS-induced stimulation of hyaluronic acid synthesis accompanied by significant decrease (20% P less than 0.05-P less than 0.01) in the interaction between GAGPS and the surface of the synovial membranes. Dermatan sulfate having a chondroitin-type structure also stimulated hyaluronic acid synthesis but this effect was not additive to the stimulation of hyaluronic acid synthesis by GAGPS. Heparin had no effect on either the basal hyaluronic acid synthesis or the GAGPS-induced stimulation of hyaluronic acid synthesis. These results indicate that binding of GAGPS to certain distinct protein components on the surface of synovial membranes is involved in the stimulatory mechanism of hyaluronic acid synthesis by GAGPS, and that the binding may be mediated by Ca2+ ion. The binding was also found to be specific for sulfated glycosaminoglycans having a chondroitin-type structure.
The index for hip disease (ISH) was established, validated and appraised as a new assessment test for the trial of new drugs as well as for long-term follow-up of patients, and to help with future indications for surgery. The ISH deals with pain, maximum walking distance, and some activities of daily living. Inter-observer reproducibility is good (mean deviation 0.55 points; p less than 0.05). In a short-term, double-blind crossover trial, the ISH, judged according to its power to distinguish between the active drug period and the placebo period, appears as one of the best assessment tests. In the long term, total hip prosthesis is most often justified when the ISH score reaches 10-12 points. The index of severity for knee disease (ISK) was validated and appraised by the same statistical methods. Its value in non-steroidal anti-inflammatory drug (NSAID) or analgesic trials is lower than the value of the ISH. However, its use is still justified for that purpose, and for long-term follow-up of osteoarthritis of the knee.
Article
The effect of various sulfated glycosaminoglycans on glycoconjugates syntheses in synovial membranes of rabbit knee joints in culture was investigated by two different approaches. In the first approach, synovial membranes isolated from rabbit knee joints were cultured in the presence of sulfated glycosaminoglycans and [14C]glucosamine. In the second approach, solutions of sulfated glycosaminoglycans were injected into rabbit knee joints and synovial membranes isolated from the joints were cultured in the presence of [14C]glucosamine. The major part of [14C]glucosamine-labeled glycoconjugates associated with the synovial membranes and secreted into culture medium was hyaluronic acid. Of the natural glycosaminoglycans tested, dermatan sulfate gave the maximum stimulation of hyaluronic acid synthesis followed by chondroitin 4- and 6-sulfate. Heparin, heparan sulfate, keratan sulfate, keratan polysulfate, and hyaluronic acid had no significant effect. Of the chemically polysulfated glycosaminoglycans, GAGPS (a persulfated derivative of chondroitin sulfate) gave high stimulation but N-acetylchitosan 3,6-disulfate had no effect. The effect of sulfated glycosaminoglycans on hyaluronic acid synthesis was the same in both experimental approaches. The increase in the amount of secreted hyaluronic acid in culture medium paralleled that in synovial membranes. The results indicate that the galactosamine-containing sulfated glycosaminoglycans have a specific stimulatory effect on hyaluronic acid synthesis. A high degree of sulfation of the molecules appeared to potentiate the stimulatory effect.
Article
The present study uses data from a national, community-based survey to compare the social impact of and medical care use due to 4 musculoskeletal conditions: rheumatoid arthritis, osteoarthritis, lower back pain, and tendinitis. The study also compares the impacts experienced by persons with these conditions with those experienced by a sample of persons having a broader range of musculoskeletal conditions, and by an age-adjusted sample representing the entire U.S. population. Rheumatoid arthritis leads to the most frequent use of physician services; lower back pain results in the most hospitalizations and surgery. Rheumatoid arthritis also causes the most restriction in activity. We found that as a broad group, persons with musculoskeletal disease experience about the same amount of restriction in activity and use about the same amount of medical care as U.S. citizens as a whole. This study demonstrates that health planning on the basis of specific musculoskeletal conditions is necessary to serve the disparate needs of persons with particular, discrete conditions.
Article
Intra-articular administration of hyaluronic acid (Hyaluronan) (HA) is now gaining widespread acceptance for the treatment of osteoarthritis (OA), even though little is known of its mechanism of action. In vitro and in vivo studies have shown that HA is able to modulate a variety of cellular functions, suppress the activities of pro-inflammatory mediators and can attenuate the nociceptive response in arthritic joints. However, recent studies with animal models of non-inflammatory OA have questioned the ability of HA to protect articular cartilage degeneration directly. The objective of this review is to examine some aspects of HA chemistry and pharmacology in relation to its interactions with cells, cartilage and the components of synovial fluid.
Article
Viscosupplementation (restoring the rheological properties of a tissue matrix) by injection of hyaluronan into the joints has been in use for 2 decades, mostly for osteoarthritis (OA) of the knee, using doses of 20-25 mg of hyaluronan of 500,000 to 2,500,000 M(r), in sequences of 2 to 10 weekly injections. Pain relief appears in a few days, progresses over a few weeks, and often lasts several months. Some data suggest the benefit can last 6 months to one year. Tolerance is universally reported as very good. Those responding to hyaluronan are 65-80%, compared to 30-35% responding to control. Compared to local steroid injections, the effect of hyaluronan appears significantly more lasting. More highly viscoelastic preparations of hyaluronan can be expected to make this therapy even more attractive.
Article
Cross-sectional data from the Medical Outcomes Study (MOS) were analyzed to test the validity of the MOS 36-Item Short-Form Health Survey (SF-36) scales as measures of physical and mental health constructs. Results from traditional psychometric and clinical tests of validity were compared. Principal components analysis was used to test for hypothesized physical and mental health dimensions. For purposes of clinical tests of validity, clinical criteria defined mutually exclusive adult patient groups differing in severity of medical and psychiatric conditions. Scales shown in the components analysis to primarily measure physical health (physical functioning and role limitations-physical) best distinguished groups differing in severity of chronic medical condition and had the most pure physical health interpretation. Scales shown to primarily measure mental health (mental health and role limitations-emotional) best distinguished groups differing in the presence and severity of psychiatric disorders and had the most pure mental health interpretation. The social functioning, vitality, and general health perceptions scales measured both physical and mental health components and, thus, had the most complex interpretation. These results are useful in establishing guidelines for the interpretation of each scale and in documenting the size of differences between clinical groups that should be considered very large.
Article
Hyaluronic acid is a natural component of cartilage and is considered not only as a lubricant in joints but also as playing a physiological role in the trophic status of cartilage. Hyalectin, a selected fraction of hyaluronic acid extracted from cocks' combs, has exhibited efficacy in animal models of osteoarthritis. To assess the efficacy and tolerability of intra-articular injections of hyalectin, we conducted a prospective, randomized, placebo-controlled trial of 1 years' duration in 110 patients with painful hydarthrodial osteoarthritis of the knee. At entry and once a week for 3 weeks, aspiration of the knee effusion and intra-articular injections of either hyalectin 20 mg (H) or its vehicle (C) were performed. The vehicle acted as the control treatment. Four weeks after the last injection, the improvement was greater in the H group compared with the C group (pain: -35.5 +/- 26.4 mm vs -25.8 +/- 21.4, P = 0.03, Lequesne's functional index: -3.8 +/- 4.3 vs -2.3 +/- 3.3, P = 0.03). During the 1 year follow-up, the need to perform supplementary local therapies (joint fluid aspiration because of painful hydarthrodial episodes and/or local corticosteroid injections) was more frequent in group C (44% vs 30%, P = 0.03). Moreover, at the final visit, the physician's overall assessment of efficacy was in favor of H (77% vs 54%, P = 0.01) and the improvement in the functional index was greater in group H (-4.4 +/- 5.1 vs -2.7 +/- 4.1, P = 0.05). This study suggests that intra-articular injections of hyalectin may (1) improve clinical condition and (2) have a long-term beneficial effect in patients with osteoarthritis of the knee.
Article
Not surprisingly in view of its unusual molecular properties, hyaluronan confers remarkable physical properties on synovial fluid. The fluid is highly viscous, non-Newtonian and a good hydrodynamic lubricant at low loads. In addition a novel role was recently described. Hyaluronan greatly depresses the rate of loss of fluid from a joint cavity when intra-articular pressure is raised. The available evidence indicates that this action is not simply a viscous one but is caused by increases in the outflow resistance of the synovial lining upon raising intra-articular pressure in the presence of intra-articular hyaluronan (McDonald & Levick, 1994, 1995). Although the cell layer of the synovial lining is discontinuous, with between a fifth and a third of the surface occupied by intercellular space, this space is occupied by a complex matrix of fibrils, microfibrils, proteoglycans and glycoproteins. The interstitial matrix has an estimated ‘pore’ radius of 15–45 nm (mean hydraulic radius; Levick, Price & Mason, 1996), which is considerably smaller than the radius of the hydrated hyaluronan domain. It has been proposed, therefore, that synovial interstitium is less permeable to hyaluronan than to water and ‘small’ solutes like albumin, with the result that hyaluronan accumulates near the surface during outflow from the joint cavity. This could create a resistive filtercake of hyaluronan molecules and buffer the outflow in the manner observed experimentally. The crucial feature of the hypothesis was that hyaluronan should escape from the joint cavity less freely than water or intra-articular albumin.
Article
To determine efficacy and safety of intraarticular (IA) hyaluronic acid (HA; Hyalgan) versus placebo and a nonsteroidal antiinflammatory drug for osteoarthritis (OA) of the knee. A series of 5 weekly IA injections of HA (20 mg each) was compared to placebo or oral naproxen in a 26 week, double blind, masked observer, multicenter trial of 495 patients with idiopathic OA. Acetaminophen was permitted for escape analgesia. The primary measurement was pain experienced on a 50 foot walk test for those completing the study (completers) as measured on a 10 cm visual analog scale (VAS). Also measured were the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index (pain, stiffness, function) and categorical assessments of pain. Patients receiving HA improved more with respect to pain on the 50 foot walk compared to placebo at Week 26 (HA vs placebo difference 8.8 mm; p < 0.005); 56% of HA treated patients compared to 41 % of placebo treated patients had > or = 20 mm reduction in the VAS from Week 5 continuously through Week 26 (p=0.031). At 26 weeks, more HA treated patients (47.6%) had slight pain or were pain-free in contrast to placebo treated (33.1%; p=0.039) or naproxen treated (36.9%; p=0.22) [corrected] patients. Improvement in secondary outcome variables was generally superior in the HA group compared to those receiving placebo and was significantly better at Week 26 with respect to the WOMAC pain (p=0.041) and WOMAC physical function (p=0.047) subscales. The HA group also tended to have better results relative to the naproxen group in both primary and secondary assessments. For all randomized patients, there was a > or = 20 mm improvement in pain experienced on the 50 foot walk in 28% [corrected] of placebo treated patients vs 36% [corrected] of the HA treated patients (p=0.127; 67% of patients completed the trial). Injection site pain, more commonly reported in the HA group (38/164=23%) than in the placebo group (22/168=13%; p < 0.001), resulted in withdrawal in 6 patients (4%). One withdrawal was associated with the HA injection (< 1%). Gastrointestinal adverse events were significantly more common in the naproxen group than the HA or the placebo groups and 14 naproxen treated patients (8.3%) discontinued prematurely due to these events. This large, controlled randomized clinical trial confirms that 5 weekly IA injections of HA (Hyalgan) in patients with OA of the knee are generally well tolerated, provide sustained relief of pain and improved patient function, and were at least as effective with fewer adverse reactions as continuous treatment with naproxen for 26 weeks.
Article
High-molecular-weight hyaluronic acid (HA) produced by the synovium may function physiologically to aid preservation of cartilage structure and prevent arthritic pain; both the size and concentration of HA in synovial fluid are diminished in osteoarthritis (OA). Glucosamine therapy for OA can be expected to increase synovial HA production by providing rate-limiting substrate. In addition, certain sulfated glycosaminoglycans and polysaccharides - including chondroitin sulfate (CS), dermatan sulfate, and pentosan polysulfate - stimulate synovial HA production, apparently owing to a hormone-like effect triggered by the binding of these polymers to membrane proteins of synovial cells. Surprisingly, a significant proportion of orally administered CS is absorbed as intact polymers - apparently by pinocytosis. These considerations may rationalize clinical studies concluding that oral CS provides slow-onset but durable pain relief and functional improvement in OA. The possibility that oral glucosamine and CS may interact in a complementary or synergistic fashion to improve synovial fluid HA content in OA should be assessed in clinical studies, and the potential of adjunctive CS administration to improve the clinical response achievable with optimal intakes of glucosamine should likewise be evaluated. In light of the fact that the synovium virtually functions as a 'placenta' for cartilage, focusing on synovium as the target for therapeutic intervention in OA may be a rational strategy.
Article
The goal of this study was to determine whether or not the intraarticular administration of hyaluronic acid can improve functional parameters, such as isokinetic muscle strength or total work and clinical test results in patients with osteoarthritis (OA) of the knee. As part of a prospective, controlled study 43 patients with osteoarthritic changes of both knees (radiographic Kellgren stage II-III) were followed in a right/left comparison. The influence of intraarticularly injected hyaluronic acid (20mg hyaluronic acid/2ml Hyalart) on functional and clinical parameters was analysed. We used the isokinetic system Cybex 600 for measuring maximal isokinetic muscle strength and total work. A total of 20 males and 23 females fulfilled the inclusion criteria with an age between 55-78 years and underwent five injections of hyaluronic acid (one injection per week). The injected knee represented the treatment group, while the contralateral knee served as the control. The maximum peak torque of the knee extensors in the treatment group was measured between 57+/-26.15/32.33+/-19.63Nm prior to the injections and 77.17+/-32.54/47.83+/-21.43Nm following the hyaluronic acid therapy (P< 0.01). The analysis of the knee flexors at angular velocities of 60 degrees /s and 180 degrees /s revealed values of 40.44+/-21.58/22.89+/-16.64Nm and 53.55+/-24.26/34.05+/-17.37Nm (P< 0.01) respectively. The evaluation of the total work of the knee flexors and extensors revealed a significant difference (P< 0.01) between the treatment and control group. The Lequesne score was reduced from 13.57+/-1.88 prior to the injections to 7.94+/-2.53 after the treatment (P< 0.01). The pain score was documented with the help of a visual analog scale. The VAS values were reduced at rest from 3.83+/-1.72cm to 1.36+/-1.42cm and during weight bearing from 7.57+/-1.34cm to 3.75+/-1.32cm in the treatment group (P< 0.01). This controlled prospective clinical trial confirmed that 5 weekly intraarticular injections of HA (Hyalart) in patients with OA of the knee provide pain relief and functional improvements.
Article
To investigate the relations between cross-sectional area and concentric and eccentric torques in the quadriceps and hamstring muscles and to determine how functional capacity relates to pain, muscle mass, and concentric and eccentric knee torques in women who have bilateral osteoarthritis (OA) of the knee. Randomized, descriptive study. A university exercise physiology laboratory in Turkey. Eighteen women with bilateral knee OA (grades 2 or 3) graded radiographically. Not applicable. Selected functional tests included the 15-m walk, rising from a chair, descending stairs, and stair climbing. Pain during the functional tests was subjectively measured on an 11-point scale (range, 0-10). Concentric and eccentric torques of the quadriceps and hamstring muscles were measured by isokinetic dynamometry with angular velocities of 60 degrees, 120 degrees, and 180 degrees /s; cross-sectional areas of the quadriceps and hamstring muscles were measured by computed tomography. Eccentric torque was significantly (P range, <.05 to.001) greater than concentric torque for the quadriceps (range, 16%-100%) and hamstring (range, 50%-158%) muscles at all angular velocities. Torque-velocity curves for concentric and eccentric contractions were almost identical to those found in healthy young and elderly people. According to r(2) values, cross-sectional area of the quadriceps and hamstring muscles explained 24% to 61% (r(2) range,.24-.61) and 38% to 51% (r(2) range,.38-.51) of the variations in concentric and eccentric peak torques, respectively. Very small to moderate correlations (.01-.75) were observed among torque at any velocity and the variables of functional capacity and pain. For stair-climbing times, the best predictor variable was the eccentric hamstring to concentric quadriceps torque ratio. For stair descending, it was the concentric hamstring to eccentric quadriceps torque ratios. These torque ratios explained 81% (r(2)=.81) and 61% (r(2)=.61) of the variations, respectively. The findings in a patient group with bilateral OA of the knee showed that (1) eccentric torque is greater than concentric torque in knee muscles; (2) the correlation coefficients (r) between concentric and eccentric torques at different velocities (r range,.63-.86), but not between reciprocal torque ratios (r range,.02-.69), are good; (3) cross-sectional area cannot be considered as a single predictor of peak torque for either quadriceps or hamstring muscles; and (4) the variation in descending stairs and stair-climbing capacities can be explained by the reciprocal torque ratios of knee muscles.
Article
To examine the gait patterns and the sagittal ground reaction forces (GRFs) in persons with knee osteoarthritis (OA) after intra-articular injection of hyaluronate and to investigate the duration of its treatment effectiveness. Case-comparison study. Gait laboratory in a tertiary care center. Fifteen subjects (30 knees) with symptomatic knee OA (stage I or II, according to the Ahlbäck grading system), and 15 age-, mass-, and gender-matched non-OA control subjects (30 knees). After initial gait analysis, the group with knee OA received 5 weekly intra-articular injections of hyaluronate to bilateral knees. Gait analysis was performed again for the group with knee OA after the completion of hyaluronate injections. Forceplate sagittal GRFs and gait parameters of velocity, cadence, step length, and stride time. The distinctive 2-peak force vector GRF was lost in persons with knee OA. The first peak rise time was significantly delayed (P<.05). The group with knee OA also revealed slower walking velocity and cadence, as well as longer stride time, than the control group (P<.05). The distinctive 2-peak force vector GRF diagram could be recovered in patients with knee OA after the completion of hyaluronate injections. Gait patterns and GRFs improved significantly after intra-articular knee injection of hyaluronate in persons with Ahlbäck stages I and II knee OA. The clinical treatment effect was immediate and may last for 6 months or more.
Article
Glucosamine and chondroitin are alternative solutions to previous pharmaceutical options for the treatment of osteoarthritis. This article describes the mechanisms of action, pharmacokinetics, recent findings, and upcoming studies of these two natural remedies. The majority of studies on the mechanisms behind glucosamine and chondroitin have been performed in vitro or on animal models; however, the results have shown favorable effects on the balance between cartilage matrix synthesis and degradation. The pharmacokinetics of the three main forms of glucosamine were compared, and glucosamine hydrochloride displayed the greatest compound purity, despite the compounds having equal oral absorption rates of 90%. Chondroitin sulfate has been the principal clinical formulation with a slightly lower oral absorption of 70%. Clinical trials were evaluated based on two categories-radiographic changes and symptom improvement of pain and function. Although adverse effects of these two remedies were minor, the quality and labeled quantity of these relatively unregulated products must be considered. More randomized controlled studies on humans in vivo need to evaluate the efficacy, long-term effects, and quality of these compounds.