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The CNS Theory of Osteoarthritis: Opportunities Beyond the Joint
Abstract
Osteoarthritis (OA) is a leading cause of global disability that affects more than half of the population over 65. It is not a single disease but a progressive, inflammatory- and immune-altering multi-disease that affects the whole joint. OA has many risk factors including age, obesity, gender, lifestyle, joint morphology, metabolic dysfunction and genetic disposition. A major stumbling block in treating clinical OA has been the inability to detect its early onset and disease progression. This gap in understanding may arise from our failure to recognize that the OA patient exhibits a vulnerability to dysregulation of central feedback circuits that control sympathetic tone, inflammation, circadian rhythms (central and peripheral clocks), gut microbiome, metabolic redox and whole joint pathology. Early detection of OA and slowing its progression may come from discoveries outside the joint targeting these potentially modifiable upstream targets. We argue that future treatments may benefit from moving from a knee-centric viewpoint to a more systems-based, whole-body approach. The challenge, however, will be to better characterize these key circuits and apply this knowledge to develop new therapies and interventions.
... Under healthy conditions, the effects of the sympathetic and the parasympathetic division are wellbalanced, resulting in homeostasis of physiological processes, such as heartbeat, blood pressure, respiration, digestion, or regulation of body temperature, and sexual arousal [3,4]. Already a minimal disturbance of this fine-tuned function can result in a variety of pathological conditions [5]. ...
... The number of patients suffering from such pathologies has increased dramatically over the last 3 decades, and therefore, it is indispensable to better understand the exact mechanisms of how pathophysiological factors contribute to their initiation and progression [12]. Osteoarthritis (OA) is a chronic degenerative and mild inflammatory disease that is often accompanied by numerous comorbidities [5,13]. It manifests itself in a reduced quality of life and, accordingly, in enormous socioeconomic costs. ...
... Moreover, depression was detected in 14% of OA patients [170]. In general, 25% of OA patients exhibited three or four additional disorders, indicating the risk for multi-morbidity in OA [5]. Since above-mentioned comorbidities are also mild chronic inflammatory diseases, an OA therapy using different anti-inflammatory drugs might reduce their symptoms as well [171][172][173][174][175] (Fig. 4). ...
The sympathetic nervous system (SNS) is a major regulatory mediator connecting the brain and the immune system that influences accordingly inflammatory processes within the entire body. In the periphery, the SNS exerts its effects mainly via its neurotransmitters norepinephrine (NE) and epinephrine (E), which are released by peripheral nerve endings in lymphatic organs and other tissues. Depending on their concentration, NE and E bind to specific α- and β-adrenergic receptor (AR) subtypes and can cause both pro- and anti-inflammatory cellular responses. The co-transmitter neuropeptide Y (NPY), adenosine triphosphate (ATP) or its metabolite adenosine are also mediators of the SNS. Local pro-inflammatory processes due to injury or pathogens lead to an activation of the SNS, which in turn induces several immunoregulatory mechanisms with either pro- or anti-inflammatory effects depending on neurotransmitter concentration or pathological context. In chronic inflammatory diseases, the activity of the SNS is persistently elevated and can trigger detrimental pathological processes. Recently, the sympathetic contribution in mild chronic inflammatory diseases like osteoarthritis (OA) attracted growing interest. OA is a whole-joint disease and is characterized by a mild chronic inflammation in the joint. In this narrative article, we summarize the underlying mechanisms behind the sympathetic influence on inflammation during OA pathogenesis. In addition, OA comorbidities also accompanied by mild chronic inflammation, such as hypertension, obesity, diabetes, and depression, will be reviewed. Finally, the potential of SNS-based therapeutic options for the treatment of OA will be discussed.
... The suggestion implied by this description was that the CNS could be functionally involved in the pathogenesis of OA. Contemporarily, this theory is revived insofar as there is the proposal of low-grade infection regulated top-down by a setpoint, as Morris et al. [84] state, that adjusts the neural, hormonal, inflammatory, and immune tone. The synovium and other joint structures are innervated by sympathetic and sensory fibers projecting to the thalamus and diencephalon. ...
... The synovium and other joint structures are innervated by sympathetic and sensory fibers projecting to the thalamus and diencephalon. The higher the autonomic tone, the fewer anti-inflammatory effects of the parasympathicus are being brought to bear [84]. On the contrary, total knee arthroplasty is apparently associated with increased levels of circulating noradrenaline and adrenaline [85]. ...
... On the contrary, total knee arthroplasty is apparently associated with increased levels of circulating noradrenaline and adrenaline [85]. This high sympathetic tone leads to increased output of neutrophils and inflammatory monocytes from the bone marrow, cytokine production, and a heightened cell-mediated immune response [84]. ...
Abstract: Introduction: Chronic pain is a multifaceted disorder genuinely entangled with psychic
and psychosomatic symptoms, which are typically involved in the processes of chronification. The
impingement syndrome of the shoulder is no exception to this rule, but several studies have shown
respective peculiarities among those with pain and impingement of the shoulder. Notably, chronic
pain is a lateralized experience, and, similarly, its psychosomatic correlates may be attached to the
hemispheres functionally. Aim: The present review therefore gives an overview of the respective
findings, with regard not only to psychopathology, but also to personality factors and psychologic
trauma, since the latter are reportedly associated with chronic pain. Moreover, we acknowledge
symmetry as a possible pathogenic factor. Methods: This narrative review followed the current
standards for conducting narrative studies. Based on prior findings, our research strategy included
the relevance of psychotraumatologic and symmetrical aspects, as well as comorbidity. We retrieved
the relevant literature reporting on the impact of psychopathology as well as personality features
on shoulder pain, as published up to January 2022 from the Medline database (1966–2022). Study
selecton: We included numerous studies, and considered the contextual relevance of studies referring
to the neuropsychosomatics of chronic pain. Results: Pain-specific fears, depression, and anxiety are
important predictors of shoulder pain, and the latter is generally overrepresented in those with trauma
and PTSD. Moreover, associations of shoulder pain with psychological variables are stronger as
regards surgical therapies as compared to conservative ones. This may point to a specific and possibly
trauma-related vulnerability for perioperative maladaptation. Additionally, functional hemispheric
lateralization may explain some of those results given that limb pain is a naturally lateralized
experience. Not least, psychosocial risk factors are shared between shoulder pain and its physical
comorbidities (e.g., hypertension), and the incapacitated state of the shoulder is a massive threat to
the function of the human body as a whole. Conclusions: This review suggests the involvement of
psychosomatic and psychotraumatologic factors in shoulder impingement-related chronic pain, but
the inconclusiveness and heterogeneity of the literature in the field is possibly suggestive of other
determinants such as laterality.
... The ACL injury phenotype is defined as a proinflammatory, procoagulopathic, proadhesive, prooxidative, profibrotic, procatabolic, and chondral degradative phenotype with neuromuscular and functional deficits. 29,41,42 Following injury, the joint becomes a chaotic milieu of "damage" signals, which include DNA modifiers, inflammatory amplifiers, injury inducers, degradative enzymes, and cartilage breakdown markers (Fig. 2). 1,42,43 The type of injury phenotype appears to be dependent on many factors including the severity of ACL injury and extent of trauma to other joint issues, health of the patient, history of pre-existing injury, timing of surgery, sex and age, graft type and positioning, infection status, and postoperative rehabilitation practices. ...
... 29,41,42 Following injury, the joint becomes a chaotic milieu of "damage" signals, which include DNA modifiers, inflammatory amplifiers, injury inducers, degradative enzymes, and cartilage breakdown markers (Fig. 2). 1,42,43 The type of injury phenotype appears to be dependent on many factors including the severity of ACL injury and extent of trauma to other joint issues, health of the patient, history of pre-existing injury, timing of surgery, sex and age, graft type and positioning, infection status, and postoperative rehabilitation practices. 1,44,45 ...
... Hay and colleagues 70 Currently there is no effective drug therapy that creates a "permissive environment" to prevent synovial and cartilage stress and reduce secondary complications. We argue that the lack of progress in this area is related to present day treat-as-you-go approach, 42,65,66 which can lead to what U.S. surgeon William C. Shoemaker called: "an uncoordinated and sometimes contradictory therapeutic outcome." 71 This mindset appears to be a by-product of highly reductionist thinking. ...
Introduction
Anterior cruciate ligament (ACL) rupture in military personnel and civilians can be a devastating injury. A service member is 10 times more likely to suffer an ACL injury than their civilian counterparts, and despite successful surgical stabilization, 4%-35% will develop arthrofibrosis, over 50% will not return to full active duty, and up to 50% will develop post-traumatic osteoarthritis (PTOA) within 15 years. Equally concerning, woman are 2 to 8 times more likely to experience ACL injuries than men, which represents a major knowledge gap.
Materials and Methods
A comprehensive literature search was performed in December 2021 using structured search terms related to prevalence, risk factors, disease progression, and treatment of ACL injury and reconstruction. The literature search was conducted independently by two researchers using PubMed, Cochrane, and Embase databases, with inclusion of articles with military, civilian, and sex relevance, and exclusion of most papers with a publication date greater than 10 years. The resources used for the review reflect the most current data, knowledge, and recommendations associated with research and clinical findings from reliable international sources.
Results
Currently, there is no effective system-based drug therapy that creates a “permissive environment” to reduce synovial and cartilage stress after ACL injury and reconstruction and prevent secondary complications. We argue that progress in this area has been hampered by researchers and clinicians failing to recognize that (1) an ACL injury is a system’s failure that affects the whole joint, (2) the early molecular events define and perpetuate different injury phenotypes, (3) male and female responses may be different and have a molecular basis, (4) the female phenotype continues to be under-represented in basic and clinical research, and (5) the variable outcomes may be perpetuated by the trauma of surgery itself. The early molecular events after ACL injury are characterized by an overexpression of joint inflammation, immune dysfunction, and trauma-induced synovial stress. We are developing an upstream adenosine, lidocaine, and magnesium therapy to blunt these early molecular events and expedite healing with less arthrofibrosis and early PTOA complications.
Conclusions
ACL injuries continue to be a major concern among military personnel and civilians and represent a significant loss in command readiness and quality of life. The lack of predictability in outcomes after ACL repair or reconstruction underscores the need for new joint protection therapies. The male–female disparity requires urgent investigation.
... For example, in people with OA, those who are inactive are more likely than those who are active to believe that they are physically unable to exercise and that physical activity is unsafe [10,11]. Further, people with knee OA often focus heavily on pain and hold beliefs that OA is an incurable, progressive 'bone-on-bone' disease, caused by 'wear-and-tear' [12,13]; perspectives refuted by contemporary scientific evidence [14][15][16][17][18]. Given such beliefs, it is perhaps unsurprising that people with knee OA generally report increased levels of fear of movement itself and of movement-induced injury [19,20] and report uncertainty as to whether undertaking physical activity will be helpful for them [21]. ...
... We undertook a feasibility pilot study of a PSE-driven individualised education and walking program for people with knee OA [42]. The OA PSE intervention drew from established 'Explain Pain' programs (originally developed for back pain; see Moseley & Butler for an overview [29]), that were then modified to include contemporary understanding of the science of OA [16,17,43], including the impact of movement and loading of the knee joints [15,18,44]. The PSE intervention had high levels of participant-rated credibility and acceptability, with promising effects on pain knowledge and clinical outcomes of pain, function, and physical activity levels [42]. ...
... Both intervention groups receive consistent, standardised general OA/activity education, graded walking and strengthening components, but have a contrasting OA pain education component. The EPIPHA-KNEE group receives contemporary PSE underpinned by principles of self-regulated learning and conceptual change theory [29,[51][52][53] and modified to integrate contemporary biological science of OA [14,16,17,43,44]. The Best Practice Control group receives best practice OA education, consistent with OA management clinical practice guidelines [31]. ...
Background
Despite well-established benefits of physical activity for knee osteoarthritis (OA), nine of ten people with knee OA are inactive. People with knee OA who are inactive often believe that physical activity is dangerous, fearing that it will further damage their joint(s). Such unhelpful beliefs can negatively influence physical activity levels. We aim to evaluate the clinical- and cost-effectiveness of integrating physiotherapist-delivered pain science education (PSE), an evidence-based conceptual change intervention targeting unhelpful pain beliefs by increasing pain knowledge, with an individualised walking, strengthening, and general education program.
Methods
Two-arm, parallel-design, multicentre randomised controlled trial involving 198 people aged ≥50 years with painful knee OA who do not meet physical activity guideline recommendations or walk regularly for exercise. Both groups receive an individualised physiotherapist-led walking, strengthening, and OA/activity education program via 4x weekly in-person treatment sessions, followed by 4 weeks of at-home activities (weekly check-in via telehealth), with follow-up sessions at 3 months (telehealth) and 5 and 9 months (in-person). The EPIPHA-KNEE group also receives contemporary PSE about OA/pain and activity, embedded into all aspects of the intervention. Outcomes are assessed at baseline, 12 weeks, 6 and 12 months. Primary outcomes are physical activity level (step count; wrist-based accelerometry) and self-reported knee symptoms (WOMAC Total score) at 12 months. Secondary outcomes are quality of life, pain intensity, global rating of change, self-efficacy, pain catastrophising, depression, anxiety, stress, fear of movement, knee awareness, OA/activity conceptualisation, and self-regulated learning ability. Additional measures include adherence, adverse events, blinding success, COVID-19 impact on activity, intention to exercise, treatment expectancy/perceived credibility, implicit movement/environmental bias, implicit motor imagery, two-point discrimination, and pain sensitivity to activity. Cost-utility analysis of the EPIPHA-KNEE intervention will be undertaken, in addition to evaluation of cost-effectiveness in the context of primary trial outcomes.
Discussion
We will determine whether the integration of PSE into an individualised OA education, walking, and strengthening program is more effective than receiving the individualised program alone. Findings will inform the development and implementation of future delivery of PSE as part of best practice for people with knee OA.
Trial registration
Australian New Zealand Clinical Trials Registry: ACTRN12620001041943 (13/10/2020).
... Every day we inhale hundreds of thousands of bacteria per cubic meter of air, and many of these inhabit our nasal-pharyngeal passages (63). These friendly "foreigners" contribute to our immune health as part of the gut-brain-immune axis (64), and have the potential to become pathogenic when a breach occurs from ischemia, trauma or disease (62). ...
... We have argued elsewhere that acute changes in the HPA axis-sympathetic-parasympathetic outflows are associated with immune dysfunction following different trauma states and sepsis (11,12), and responsible for "low-level" persistent inflammation in most chronic inflammatory diseases, such as osteoarthritis and cardiovascular diseases (61,64). Recent studies further demonstrate that the vagus nerve can modulate the host immune response after an infectious or sterile barrier breach (126,168,173), which may also have feedback inputs from changes to the CNS-gut-microbiome-immune axis (61,64,177). ...
... We have argued elsewhere that acute changes in the HPA axis-sympathetic-parasympathetic outflows are associated with immune dysfunction following different trauma states and sepsis (11,12), and responsible for "low-level" persistent inflammation in most chronic inflammatory diseases, such as osteoarthritis and cardiovascular diseases (61,64). Recent studies further demonstrate that the vagus nerve can modulate the host immune response after an infectious or sterile barrier breach (126,168,173), which may also have feedback inputs from changes to the CNS-gut-microbiome-immune axis (61,64,177). Increased vagal outflow to the spleen leads to reduced activation of circulating neutrophils by modulating the expression of CD11b (146). ...
We present a brief history of the immune response and show that Metchnikoff’s theory of inflammation and phagocytotic defense was largely ignored in the 20th century. For decades, the immune response was believed to be triggered centrally, until Lafferty and Cunningham proposed the initiating signal came from the tissues. This shift opened the way for Janeway’s pattern recognition receptor theory, and Matzinger’s danger model. All models failed to appreciate that without inflammation, there can be no immune response. The situation changed in the 1990s when cytokine biology was rapidly advancing, and the immune system’s role expanded from host defense, to the maintenance of host health. An inflammatory environment, produced by immune cells themselves, was now recognized as mandatory for their attack, removal and repair functions after an infection or injury. We explore the cellular programs of the immune response, and the role played by cytokines and other mediators to tailor the right response, at the right time. Normally, the immune response is robust, self-limiting and restorative. However, when the antigen load or trauma exceeds the body’s internal tolerances, as witnessed in some COVID-19 patients, excessive inflammation can lead to increased sympathetic outflows, cardiac dysfunction, coagulopathy, endothelial and metabolic dysfunction, multiple organ failure and death. Currently, there are few drug therapies to reduce excessive inflammation and immune dysfunction. We have been developing an intravenous (IV) fluid therapy comprising adenosine, lidocaine and Mg²⁺ (ALM) that confers a survival advantage by preventing excessive inflammation initiated by sepsis, endotoxemia and sterile trauma. The multi-pronged protection appears to be unique and may provide a tool to examine the intersection points in the immune response to infection or injury, and possible ways to prevent secondary tissue damage, such as that reported in patients with COVID-19.
... [100][101][102][103][104] These same factors are upregulated, albeit at lower levels, to perpetuate chronic disease. 105,106 In these traumatic injury and pathological states, a subject that has received little attention is the role the CNS and sympathetic/parasympathetic outflows play in linking cardiovascular function to coagulopathy and organ dysfunction. An important link in the chain is ventriculoarterial (VA) coupling, which optimizes the energy transfer of blood from the left ventricle (LV) to the systemic circulation and tissues, with minimal losses in friction and heat. ...
... 118 Change in the host's gut microbiome is bidirectionally linked to the CNS through vagal afferents, immune, and hypothalamicpituitary-adrenal axis modulation, and the CNS, in turn, can modulate the gastrointestinal tract and the enteric nervous system. 106,[118][119][120][121][122] Unfortunately, very few gut microbiome studies have been performed in severe trauma patients, although Howard et al did show rapid changes in the microbiome after trauma, which they associated with poor outcomes. 123 Further studies are required to better understand the effect of trauma on bidirectional signaling between the gut-brain axis, sympathetic tone, and TIC (►Fig. ...
Traumatic-induced coagulopathy (TIC) is often associated with significant bleeding, transfusion requirements, inflammation, morbidity, and mortality. This review considers TIC as a systems failure, not as a single-event manifestation of trauma. After briefly reviewing the meaning of TIC and the bewildering array of fibrinolysis phenotypes, we will discuss the role of platelets and fibrinogen in coagulopathy. Next, we will review the different TIC hypotheses and drill down to a single mechanistic domain comprising (1) thrombin's differential binding to thrombomodulin, (2) the expression of annexin II-S100A10 complex, and (3) the functional integrity of the endothelial glycocalyx. This triad forms the basis of the “switch” hypothesis of TIC. We will next address the potential limitations of current practice in treating a coagulation or fibrinolytic defect, and the next defect, and so on down the line, which often leads to what U.S. surgeon William C. Shoemaker considered “an uncoordinated and sometimes contradictory therapeutic outcome.” The treat-as-you-go approach using sequential, single-target treatments appears to be a by-product of decades of highly reductionist thinking and research. Lastly, we will present a unified systems hypothesis of TIC involving three pillars of physiology: the central nervous system (CNS)–cardiovascular system, the endothelial glycocalyx, and mitochondrial integrity. If CNS control of ventriculoarterial coupling is maintained close to unity following trauma, we hypothesize that the endothelium will be protected, mitochondrial energetics will be maintained, and TIC (and inflammation) will be minimized. The Systems Hypothesis of Trauma (SHOT) also helps to answer why certain groups of severely bleeding trauma patients are still dying despite receiving the best care. Currently, no drug therapy exists that targets the whole system.
... For example, higher dietary fiber intake relates with lower risk of knee pain among those with or at risk for OA (27). This finding may reflect a healthier lifestyle, higher socioeconomic status, and/or that fiber promotes a healthy body mass (28) and gut microbiome (29,30). Across adulthood, better diet quality (ie, greater consumption of fruits/vegetables, lower consumption of sugar, processed meats) was associated with better chair rise speed, standing balance time and timed-up-and-go speed (31). ...
... It is also possible though, that high fiber intake reflects healthier living and socioeconomics; but without a full version of a food frequency questionnaire in the CLSA, we were unable to assess diet quality fully. High sugar and high fat diets may alter gut microbiota in ways that worsen systemic inflammation; while high fiber diets may prevent this intestinal dysbiosis (29,30). Nonetheless, while rehabilitation that includes exercise has shown considerable improvements in pain and function for knee OA, this research highlights the potential importance of also considering specific dietary intake, notably fiber, for its impact on mobility. ...
Background
This study examined whether aspects of diet and nutrition risk explain variance in physical capacity and general health, after controlling for covariates, in Canadian adults with osteoarthritis (OA).
Methods
This was a cross-sectional study of baseline data from the Canadian Longitudinal Study on Aging (CLSA). Data from 1404 participants with hand, hip and/or knee OA were included. A series of regression analyses were conducted with independent variables of food intake (fibre and high calorie snack intake) and nutrition risk; and dependent variables of physical capacity and general health. Physical capacity was characterized through grip strength and a pooled index of four mobility tests. General health was characterized through an index of self-reported general health, mental health and healthy aging.
Results
Higher fibre intake was related to greater mobility (p=0.01). Food intake was not related to any other outcome. Nutrition risk was significantly associated with mobility (p<0.001) and general health (p<0.001); those with a high nutrition risk classification had poorer general health (p<0.001, d=0.65) than those at low nutrition risk. As well, those with moderate nutrition risk had poorer general health than those with low nutrition risk (p=0.001, d=0.31).
Conclusions
Nutrition risk screening for older adults with OA provides insight into behavioural characteristics associated with reduced mobility and poorer general health. Also, those consuming greater amounts of fibre demonstrated better mobility. Thus, this research suggests that quality of diet and nutritional behaviours can impact both physical and mental aspects of health in those with OA.
... The main clinical manifestations are knee joint pain, swelling, and functional impairment. The characteristics of osteoarthritis (OA) are cartilage degeneration, subchondral bone abnormalities, and non-specific synovitis [2]. The formation of osteoarthritis is the result of the interaction between systemic and local factors, and is the most common form of arthritis. ...
The mechanism of CFB in treating knee osteoarthritis is not yet clear and deserves further discussion. The C28/I2 cell was stimulated by TNF-α and the MIA-induced OA rat model were constructed, and then treated with a certain concentration of CFB. The effects of CFB on chondrocyte apoptosis, inflammatory response, and collagen matrix degradation were assessed. Furthermore, we analyzed the regulation of CFB on the DDIT3 and Hedgehog pathways through western blot analysis. The smoothened agonist inhibitor SAG and DDIT3 overexpression lentivirus were applied to investigate how CFB regulates DDIT3 and Hedgehog pathway to protect against osteoarthritis. Our experimental results proved the protective of CFB against TNF-α stimulated C28/I2 cells. CFB treatment downregulated the DDIT3 protein and inactivated the HH pathway in TNF-α stimulated C28/I2 cells, and this effect may be related to the DDIT3 or HH pathway. Furthermore, the inhibitory effect of CFB on the HH pathway is related to DDIT3. In vivo animal assays showed that CFB can inhibit the degradation of cartilage collagen matrix, inhibit chondrocyte apoptosis, improve chondrocyte damage, and alleviate pain in arthritis rats, and the effect of CFB on OA rats is related to the HH pathway mediated by DDIT3. In summary, CFB has significant therapeutic effects on osteoarthritis, protecting cartilage degradation and damage, and inhibiting inflammatory responses. DDIT3 may participate as an intermediate molecule in the protective effect of the drug on OA. The SHH/GLi1 pathway is regulated by CFB through DDIT3.
... Among the most prevalent chronic joint illnesses, osteoarthritis (OA) can result in joint pain, stiffness, deformity, and narrowing of the joint space, all of which have a negative effect on the patient's quality of life [1]. Osteoarthritis occurs due to various etiologies resulting in biological and morphological abnormalities [2]. ...
Background and aim. One of the most prevalent chronic joint illnesses is osteoarthritis (OA), which can impair a patient's quality of life by causing joint pain, stiffness, deformity, and narrowed joint spaces. Many factors influence the pathogenesis of Osteoarthritis such as age and body weight, as well as genetic factors that are reported to play a role in the occurrence and progression of Osteoarthritis. Recently, many studies have demonstrated that inflammatory variables contribute to osteoarthritis pathomechanisms. It is currently thought that inflammatory variables alone are an independent risk factor for osteoarthritis. Methods. Observational sub-analysis with a cross-sectional approach to examine the relationship between Angiotensin Converting Enzyme 1 (ACE 1) levels and the grading of osteoarthritis at “Dr. Wahidin Sudirohusodo” Hospital from October 2020 to February 2021. ACE 1 levels were measured using the Elisa KIT and grading of osteoarthritis using the Kellgren and Lawrence criteria. Results. Analysis of the relationship between ACE 1 levels and osteoarthritis grading using the ANOVA test and Post Hoc Bonferonni Test showed a significant relationship between ACE 1 levels and osteoarthritis grading, where high ACE 1 levels were related to osteoarthritis grading. Deficiency and insufficiency (p<0.05). The results of this study are in line with previous research. Conclusion. The higher the ACE 1 level, the more severe the degree of knee osteoarthritis.
... However, we did not differentiate between different phenotypes within the patient cohort in the present study. Therefore, some effects may have been masked by the large variability of the data [56,57]. This aspect will be addressed in future investigations using larger cohorts. ...
Background
Osteoarthritis (OA) is a chronic degenerative joint disease causing limited mobility and pain, with no curative treatment available. Recent in vivo studies suggested autonomic alterations during OA progression in patients, yet clinical evidence is scarce. Therefore, autonomic tone was analyzed in OA patients via heart rate variability (HRV) measurements.
Methods
Time-domain (SDRR, RMSSD, pRR50) and frequency-domain (LF, HF, LF/HF) HRV indices were determined to quantify sympathetic and parasympathetic activities. In addition, perceived stress, WOMAC pain as well as serum catecholamines, cortisol and dehydroepiandrosterone-sulphate (DHEA-S) were analyzed. The impact of the grade of disease (GoD) was evaluated by linear regression analysis and correlations with clinical data were performed.
Results
GoD significantly impacted the autonomic tone in OA patients. All time-domain parameters reflected slightly decreased HRV in early OA patients and significantly reduced HRV in late OA patients. Moreover, frequency-domain analysis revealed decreased HF and LF power in all OA patients, reflecting diminished parasympathetic and sympathetic activities. However, LF/HF ratio was significantly higher in early OA patients compared to late OA patients and implied a clear sympathetic dominance. Furthermore, OA patients perceived significantly higher chronic stress and WOMAC pain levels compared to healthy controls. Serum cortisol and cortisol/DHEA-S ratio significantly increased with GoD and positively correlated with WOMAC pain. In contrast, serum catecholamines only trended to increase with GoD and pain level.
Conclusions
This prospective study provides compelling evidence of an autonomic dysfunction with indirect sympathetic dominance in early and late knee OA patients for the first time based on HRV analyses and further confirmed by serum stress hormone measurements. Increased sympathetic activity and chronic low-grade inflammation in OA as well as in its major comorbidities reinforce each other and might therefore create a vicious cycle. The observed autonomic alterations coupled with increased stress and pain levels highlight the potential of HRV as a prognostic marker. In addition, modulation of autonomic activity represents an attractive future therapeutic option.
Graphical abstract
... Integration of the sensory and motor pathways within the central nervous system is critical in avoiding falls. The central nervous system has been suggested to play a critical role in the development of KOA [12]. Indeed, KOA patients appear to have impairment in the ability to mentally rehearse gait motor patterns as displayed by fMRI hypoactivation in motor planning (premotor and parietal) brain regions, the brainstem and the cerebellum [13]. ...
Purpose
Although knee Osteoarthritis (KOA) sufferers are at an increased risk of falls, possibly due to impaired gait function, the associated gaze behaviour in patients with KOA are largely unknown. Thus, we compared gait and gaze behaviours characteristics between KOA patients and asymptomatic age-matched controls.
Results
For Timed Up and Go (TUG) and stair climb tasks, the KOA group demonstrated longer periods of gaze fixations with less frequency of fixations compared to the control group. Conversely, for the Timed up and Go Agility (TUGA) test shorter fixation and frequency patterns were observed. The KOA group presented a shorter final stride length prior to the initiation of the first step in the Stair climb assessment. In addition, for the 30m walk and dual task assessments, the average step length was significantly shorter in the KOA group compared to controls.
Conclusion
Overall, we found altered gait and gaze behaviours are evident in KOA patients which could relate to their increased falls risk.
... These cytokines stimulate the production of eicosanoids and sympathetic amines that sensitize nociceptors [49]. Joint edema is the result of vasodilation and increased vascular permeability, with exudation of plasma and proteins, as well as amplification of inflammatory mechanisms in the synovial membrane [52,53,54]. I.a. ...
... Кишечная микробиота оказывает прямое и косвенное влияние на метаболизм костной ткани, влияя на усвоение витаминов, кальция, уровень половых гормонов. Короткоцепочечные жирные кислоты (SCFAs) повышают уровни фактора роста инсулина-1 (IGF-1) в сыворотке и костном мозге, таким образом кишечная микробиота оказывает анаболическое действие на костную ткань [43]. Кишечная микробиота оказывает значительное влияние на костную массу через сигнальные пути NOD1 и NOD2. ...
The potential association between dysbiosis of the gut microbiota and osteoarthritis is confirming by a growing number of studies. Given the social significance, the high prevalence of osteoarthritis, and evidences that quantitative and qualitative modification of the gut microbiota affects its progression, it seems important to clarify the underlying mechanisms of this association. Osteoarthritis is a multifactorial joint disease, which is based primarily on the progressive degeneration of articular cartilage. Impaired metabolic activity of chondrocytes, consisting in an imbalance in the extracellular matrix synthesis and degradation processes, causes the persistent release of molecular patterns associated with damage. This leads to the activation of a wide range of innate immune cells receptors and is the basis for the development of an inflammatory reaction in the joint. The involvement of macrophages in the synovial membrane and their activation leads to the production of pro-inflammatory cytokines, leading to the development of chronic low-grade inflammation in the joint, supporting the synthesis of catabolic enzymes by chondrocytes and escalating the cartilage degeneration. Microbial dysbiosis, defined as an adverse modification in the diversity, structure, or metabolic activity of the gut microbiota, is a hidden risk factor, accompanied by metabolic endotoxemia and, consequently, by increased production of pro-inflammatory cytokines, that support the systematic low-grade inflammation and pathophysiological mechanisms of osteoarthritis. It has been shown that dysbiosis of the gut microbiota intestinal takes part in the formation of other osteoarthritis risk factors for, for example, obesity and metabolic disorders. The identification of important interrelated pathophysiological mechanisms of these pathologies will contribute to the development of new pathogenetic treatment methods with their subsequent active introduction into clinical practice.
... OA (osteoarthritis) is the leading cause of disability in the elderly over the age of 65 [1]. The global age-standardized incidence rate (ASIR) of OA (compared to low back and neck pain) increased by 0.32% per year (95% CI 0.28 to 0.36), or approximately 9%, and it is worth noting that the aging of the global population has actually driven a greater increase in the absolute number of new cases of OA without standardizing on age [2]. ...
Objective:
As one of the most important protein-degrading enzymes, ADAMTS-5 plays an important role in the regulation of cartilage homeostasis, while miRNA-140 is specifically expressed in cartilage, which can inhibit the expression of ADAMTS-5 and delay the progression of OA (osteoarthritis). SMAD3 is a key protein in the TGF-β signaling pathway, inhibiting the expression of miRNA-140 at the transcriptional and post-transcriptional levels, and studies have confirmed the high expression of SMAD3 in knee cartilage degeneration, but whether SMAD3 can mediate the expression of miRNA-140 to regulate ADAMTS-5 remains unknown.
Methods:
Sprague-Dawley (SD) rat chondrocytes were extracted in vitro and treated with a SMAD3 inhibitor (SIS3) and miRNA-140 mimics after IL-1 induction. The expression of ADAMTS-5 was detected at the protein and gene levels at 24 h, 48 h, and 72 h after treatment. The OA model of SD rats was created using the traditional Hulth method in vivo, with SIS3 and lentivirus packaged miRNA-140 mimics injected intra-articularly at 2 weeks, 6 weeks and 12 weeks after surgery. The expression of miRNA-140 and ADAMTS-5 in the knee cartilage tissue was observed at the protein and gene levels. Concurrently, knee joint specimens were fixed, decalcified, and embedded in paraffin prior to immunohistochemical, Safranin O/Fast Green staining, and HE staining analyses for ADAMTS-5 and SMAD3.
Results:
In vitro, the expression of ADAMTS-5 protein and mRNA in the SIS3 group decreased to different degrees at each time point. Meanwhile, the expression of miRNA-140 in the SIS3 group was significantly increased, and the expression of ADAMTS-5 in the miRNA-140 mimics group was also significantly downregulated (P < 0.05). In vivo, it was found that ADAMTS-5 protein and gene were downregulated to varying degrees in the SIS3 and miRNA-140 mimic groups at three time points, with the most significant decrease at the early stage (2 weeks) (P < 0.05), and the expression of miRNA-140 in the SIS3 group was significantly upregulated, similar to the changes detected in vitro. Immunohistochemical results showed that the expression of ADAMTS-5 protein in the SIS3 and miRNA-140 groups was significantly downregulated compared to that in the blank group. The results of hematoxylin and eosin staining showed that in the early stage, there was no obvious change in cartilage structure in the SIS3 and miRNA-140 mock groups. The same was observed in the results of Safranin O/Fast Green staining; the number of chondrocytes was not significantly reduced, and the tide line was complete.
Conclusion:
The results of in vitro and in vivo experiments preliminarily showed that the inhibition of SMAD3 significantly reduced the expression of ADAMTS-5 in early OA cartilage, and this regulation might be accomplished indirectly through miRNA-140.
... There is increasing interest in the relationship between gut microbiota and OA. Alteration in normal gut microbiota has been implicated in metabolic syndrome and inflammation, which are also important components in the development of OA [13]. A recent work has suggested the role of gut microbiota in OA. ...
Osteoarthritis (OA) is the most common joint disease primarily characterized by cartilage degeneration. Milk-derived extracellular vesicles (mEVs) were reported to inhibit catabolic and inflammatory processes in the cartilage of OA patients. However, the current therapies target the advanced symptoms of OA, and it is significant to develop a novel strategy to inhibit the processes driving OA pathology. In this study, we investigated the therapeutic potential of mEVs in alleviating OA in vivo. The results revealed that mEVs ameliorated cartilage degeneration by increasing hyaline cartilage thickness, decreasing histological Osteoarthritis Research Society International (OARSI) scores, enhancing matrix synthesis, and reducing the expression of cartilage destructive enzymes in the destabilization of medial meniscus (DMM) mice. In addition, the disturbed gut microbiota in DMM mice was partially improved upon treatment with mEVs. It was observed that the pro-inflammatory bacteria (Proteobacteria) were reduced and the potential beneficial bacteria (Firmicutes, Ruminococcaceae, Akkermansiaceae) were increased. mEVs could alleviate the progression of OA by restoring matrix homeostasis and reshaping the gut microbiota. These findings suggested that mEVs might be a potential therapeutic dietary supplement for the treatment of OA.
... The regulatory effect of the central nervous system on OA has been discovered in recent years (Morris et al., 2019). Clinical studies have shown that the clinical manifestations of OA patients, such as pain or stiffness, are rhythmic changes (Bellamy et al., 2002). ...
Osteoarthritis (OA) is a slowly progressing and irreversible joint disease. The existing non-surgical treatment can only delay its progress, making the early treatment of OA a research hotspot in recent years. Melatonin, a neurohormone mainly secreted by the pineal gland, has a variety of regulatory functions in different organs, and numerous studies have confirmed its therapeutic effect on OA. Non-coding RNAs (ncRNAs) constitute the majority of the human transcribed genome. Various ncRNAs show significant differentially expressed between healthy people and OA patients. ncRNAs play diverse roles in many cellular processes and have been implicated in many pathological conditions, especially OA. Interestingly, the latest research found a close interaction between ncRNAs and melatonin in regulating the pathogenesis of OA. This review discusses the current understanding of the melatonin-mediated modulation of ncRNAs in the early stage of OA. We also delineate the potential link between rhythm genes and ncRNAs in chondrocytes. This review will serve as a solid foundation to formulate ideas for future mechanistic studies on the therapeutic potential of melatonin and ncRNAs in OA and better explore the emerging functions of the ncRNAs.
... Following major trauma, VA uncoupling not only affects the periphery but it can lead to hypoperfusion of the abdominal organs, including gut wall ischemia and leakiness, which can exacerbate immuno-inflammatory trajectories, immunosuppression, infectious complications and sepsis (Mayer and Gupta, 2015). Alterations in the gut microbiome is bidirectionally linked to the CNS through vagal afferents and HPA axis, and the CNS to the GI tract via the enteric nervous system (Tillisch, 2014;Mayer and Gupta, 2015;Liang and FitzGerald, 2017;Letson et al., 2019a;Dobson et al., 2019;Morris et al., 2019). In trauma patients, Howard and colleagues reported rapid changes in the microbiome following injury, which were associated with poor outcomes (Howard et al., 2017). ...
Over the years, many explanations have been put forward to explain early and late deaths following hemorrhagic trauma. Most include single-event, sequential contributions from sympathetic hyperactivity, endotheliopathy, trauma-induced coagulopathy (TIC), hyperinflammation, immune dysfunction, ATP deficit and multiple organ failure (MOF). We view early and late deaths as a systems failure, not as a series of manifestations that occur over time. The traditional approach appears to be a by-product of last century’s highly reductionist, single-nodal thinking, which also extends to patient management, drug treatment and drug design. Current practices appear to focus more on alleviating symptoms rather than addressing the underlying problem. In this review, we discuss the importance of the system, and focus on the brain’s “privilege” status to control secondary injury processes. Loss of status from blood brain barrier damage may be responsible for poor outcomes. We present a unified Systems Hypothesis Of Trauma (SHOT) which involves: 1) CNS-cardiovascular coupling, 2) Endothelial-glycocalyx health, and 3) Mitochondrial integrity. If central control of cardiovascular coupling is maintained, we hypothesize that the endothelium will be protected, mitochondrial energetics will be maintained, and immune dysregulation, inflammation, TIC and MOF will be minimized. Another overlooked contributor to early and late deaths following hemorrhagic trauma is from the trauma of emergent surgery itself. This adds further stress to central control of secondary injury processes. New point-of-care drug therapies are required to switch the body’s genomic and proteomic programs from an injury phenotype to a survival phenotype. Currently, no drug therapy exists that targets the whole system following major trauma.
... The joint is a time-sensitive organ that is partly controlled by the central rhythm in the CNS and that has its own peripheral rhythm [88]. The normal expression of rhythmic genes protects the cartilage, synovium, subchondral bone and skeletal muscle of the joint from the pathological alternation of OA. ...
Osteoarthritis (OA) is one of the main causes of disabilities among older people. To date, multiple disease-related molecular networks in OA have been identified, including abnormal mechanical loadings and local inflammation. These pathways have not, however, properly elucidated the mechanism of OA progression. Recently, sufficient evidence has suggested that rhythmic disturbances in the central nervous system (CNS) and local joint tissues affect the homeostasis of joint and can escalate pathological changes of OA. This is accompanied with an exacerbation of joint symptoms that interfere with the rhythm of CNS in reverse. Eventually, these processes aggravate OA progression. At present, the crosstalk between joint tissues and biological rhythm remains poorly understood. As such, the mechanisms of rhythm changes in joint tissues are worth study; in particular, research on the effect of rhythmic genes on metabolism and inflammation would facilitate the understanding of the natural rhythms of joint tissues and the OA pathology resulting from rhythm disturbance.
... Each center has feedback circuits from intestinal tract (gut microbiota), OA joints and cellular metabolism. Circadian rhythms, gut microbiota, metabolism and redox regulation are controlled by central feed circuits above, the dysregulation of which is involved in the progression of OA (Morris et al., 2019). In addition, some information transmitted from intestinal tract is able to be distributed to the hypothalamus, regulating appetite, food intake, and energy expenditure (Silvestre et al., 2020), which is then involved in the progression of OA through the mechanism of metabolism mentioned in the previous part. ...
Osteoarthritis (OA) is a multifactorial joint disease characterized by degeneration of articular cartilage, which leads to joints pain, disability and reduced quality of life in patients with OA. Interpreting the potential mechanisms underlying OA pathogenesis is crucial to the development of new disease modifying treatments. Although multiple factors contribute to the initiation and progression of OA, gut microbiota has gradually been regarded as an important pathogenic factor in the development of OA. Gut microbiota can be regarded as a multifunctional “organ”, closely related to a series of immune, metabolic and neurological functions. This review summarized research evidences supporting the correlation between gut microbiota and OA, and interpreted the potential mechanisms underlying the correlation from four aspects: immune system, metabolism, gut-brain axis and gut microbiota modulation. Future research should focus on whether there are specific gut microbiota composition or even specific pathogens and the corresponding signaling pathways that contribute to the initiation and progression of OA, and validate the potential of targeting gut microbiota for the treatment of patients with OA.
... Osteoarthritis (OA) is a highly prevalent rheumatic musculoskeletal disorder, encompassing progressive, inflammatory and immunological changes affecting joint structures. 1 The clinical features of OA include cartilage loss, increased subchondral bone thickness, tidemark replication, decreased subchondral trabecular bone mass and bone marrow lesions (BML). 2,3 Endogenous biological clocks determine daily, monthly or annual rhythms in biological processes. ...
Endogenous homeostasis and peripheral tissue metabolism are disrupted by irregular fluctuations in activation, movement, feeding and temperature, which can accelerate negative biological processes and lead to immune reactions, such as rheumatoid arthritis (RA) and osteoarthritis (OA). This review summarizes abnormal phenotypes in articular joint components such as cartilage, bone and the synovium, attributed to the deletion or overexpression of clock genes in cartilage or chondrocytes. Understanding the functional mechanisms of different genes, the differentiation of mouse phenotypes and the prevention of joint ageing and disease will facilitate future research.
... Given that the IFP is highly vascularized at the periphery and richly innervated with nerves and lymphatic vessels, it plays a significant role in local and systemic immune responses to surgery. For example, the IFP contains adipocytes, preadipocytes, macrophages, fibroblasts, and other cells that secrete cytokines, adipokines, and other neural, inflammatory and metabolic mediators [25] that may have protective functions beyond the joint [26]. Given that there is little experimental support that removal of the IFP reduces postoperative pain [24], ALM-induced reduction of inflammation and fibrosis may have wider significance for IFP preservation during TKA and may confer immune benefits for the patient [27]. ...
Background
There is currently no drug therapy to prevent arthrofibrosis following knee surgery. We aimed to determine if the anti-ischemic and anti-inflammatory drug adenosine, lidocaine and Mg ²⁺ (ALM), reduces surgery-related arthrofibrosis in a rat model of knee implant surgery.
Methods
Male Sprague-Dawley rats ( n = 24) were randomly divided into ALM or saline groups. The right knee of each animal was implanted with custom titanium (femur) and polyethylene (tibia) implants, and the left knee served as a non-operated control. An intra-articular ALM or saline bolus (0.1 ml) was administered at the end of surgery, and animals monitored for 4 weeks. Fibrotic changes were assessed by macroscopic examination, histopathology, and expression of key inflammatory and fibrotic markers in the joint capsule and infrapatellar fat pad (IFP).
Results
Knee swelling was evident in both groups at 4 weeks. However, range of motion was 2-fold higher in the ALM-treated knees, and differences in macroscopic pathology indicated improved healing, compared to the control group. Histologically, ALM treatment also led to significantly decreased synovitis and fibrotic pathology in the joint capsule and IFP compared to saline controls. RNA and protein expression profiles of pro-fibrotic mediators (α-SMA, TGF-β1, FGF1, PDGFA) were also significantly lower in knees from ALM-treated animals. In addition, the expression of inflammatory mediators was lower in plasma (IL-1β, IL-10) and joint tissue (NFκB, IL-1β, IL-12), 4 weeks after surgery.
Conclusion
We show that intra-articular administration of a single ALM bolus significantly decreased fibrotic pathology and synovitis in an experimental model of knee implant surgery, by blunting inflammation and modulating essential genes of fibrosis. ALM has the therapeutic potential for translation into humans undergoing knee replacement surgery.
... So far, the new components of the CNS theory in OA pathophysiology include hypothalamicpituitary (HPA) axis, nucleus tractus solitarus (NTS), hypothalamic suprachiasmatic nuclei (SCN), and other associated higher centers, and each with their own feedback circuits from the gut microbiota, OA joints, and cellular metabolism. Progression of OA is increasingly linked to dysregulation of central feedback circuits (e.g., HPA axis and NTS), which control circadian rhythm, gut microbiome, metabolism, and redox regulation [60]. ...
Osteoarthritis (OA) is one of the most frequent musculoskeletal diseases characterized by degeneration of articular cartilage, subchondral bone remodeling, and synovial membrane inflammation, which is a leading cause of global disability, morbidity, and decreased quality of life. Interpreting the potential mechanisms of OA pathogenesis is essential for developing novel prevention and disease-modifying therapeutic interventions. Gut microbiota is responsible for a series of metabolic, immunological, and structural and neurological functions, potentially elucidating the heterogeneity of OA phenotypes and individual features. In this narrative review, we summarized research evidence supporting the hypothesis of a “gut-joint axis” and the interaction between gut microbiota and the OA-relevant factors, including age, gender, genetics, metabolism, central nervous system, and joint injury, elucidating the underlying mechanisms of this intricate interaction. In the context, we also speculated the promising manipulation of gut microbiota in OA management, such as exercise and fecal microbiota transplantation (FMT), highlighting the clinical values of gut microbiota. Additionally, future research directions, such as more convincing studies by the interventions of gut microbiota, the gene regulation of host contributing to or attributed to the specific phenotypes of gut microbiota related to OA, and the relevance of distinct cell subgroups to gut microbiota, are expected. Moreover, gut microbiota is also the potential biomarker related to inflammation and gut dysbiosis that is able to predict OA progression and monitor the efficacy of therapeutic intervention.
Severe infection and sepsis are medical emergencies. High morbidity and mortality are linked to CNS dysfunction, excessive inflammation, immune compromise, coagulopathy and multiple organ dysfunction. Males appear to have a higher risk of mortality than females. Currently, there are few or no effective drug therapies to protect the brain, maintain the blood brain barrier, resolve excessive inflammation and reduce secondary injury in other vital organs. We propose a major reason for lack of progress is a consequence of the treat-as-you-go, single-nodal target approach, rather than a more integrated, systems-based approach. A new revolution is required to better understand how the body responds to an infection, identify new markers to detect its progression and discover new system-acting drugs to treat it. In this review, we present a brief history of sepsis followed by its pathophysiology from a systems’ perspective and future opportunities. We argue that targeting the body’s early immune-driven CNS-response may improve patient outcomes. If the barrage of PAMPs and DAMPs can be reduced early, we propose the multiple CNS-organ circuits (or axes) will be preserved and secondary injury will be reduced. We have been developing a systems-based, small-volume, fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat sepsis and endotoxemia. Our early studies indicate that ALM therapy shifts the CNS from sympathetic to parasympathetic dominance, maintains cardiovascular-endothelial glycocalyx coupling, reduces inflammation, corrects coagulopathy, and maintains tissue O 2 supply. Future research will investigate the potential translation to humans.
Background and aims: Today, various methods are used to evaluate the severity of knee instability in patients with knee osteoarthritis (KOA). The aim of this study was to compare the state of brain waves related to balance, pain, and proprioception among KOA women with and without knee instability.
Methods: In this cross-sectional study, 60 female KOA patients were selected, and based on the instability index scores, were divided into two groups of 30 people with and without knee instability. The pain was evaluated with visual analog scales (VAS), knee proprioception with angle reconstruction error and goniometer, balance with Berg Balance Scale (BBS), and brain wave analysis with the ProComp Infiniti device. The Fitzgerald scale was also used to assign subjects to groups with and without knee instability. Then, the two groups were compared.
Results: There was no significant difference between the mean scores of brain waves related to balance between the two groups. However, there was a significant difference between the two groups in knee proprioception at the target angles of 45° (both legs: p=0.0001) and 70° (right leg: p=0.003 and left leg: p=0.001). Also, a significant difference was observed between the two groups in balance scores (p=0.0001).
Conclusion: The evaluation of brain waves associated with balance in KOA patients cannot provide useful and practical information to identify people with knee instability. However, the sense of proprioception and balance in these people are distinct and can be factors to identify people prone to knee instability in these patients.
Little is known on the sex-specific healing responses after an anterior cruciate ligament (ACL) rupture. To address this, we compared male and female Sprague-Dawley rats following non-surgical ACL rupture. Hematology, inflammation, joint swelling, range of motion, and pain-sensitivity were analyzed at various times over 31-days. Healing was assessed by histopathology and gene expression changes in the ACL remnant and adjacent joint tissues. In the first few days, males and females showed similar functional responses after rupture, despite contrasting hematology and systemic inflammatory profiles. Sex-specific differences were found in inflammatory, immune and angiogenic potential in the synovial fluid. Histopathology and increased collagen and fibronectin gene expression revealed significant tissue remodeling in both sexes. In the ACL remnant, however, Acta2 gene expression (α-SMA production) was 4-fold higher in males, with no change in females, indicating increased fibroblast-to-myofibroblast transition with higher contractile elements (stiffness) in males. Females had 80% lower Pparg expression, which further suggests reduced cellular differentiation potential in females than males. Sex differences were also apparent in the infrapatellar fat pad and articular cartilage. We conclude females and males showed different patterns of healing post-ACL rupture over 31-days, which may impact timing of reconstruction surgery, and possibly clinical outcome.
Osteoartrit tüm dünyada en yaygın görülen kas-iskelet sistemi hastalıklarından biridir. Özellikle vücut ağırlığını taşımakla sorumlu olan kalça, diz, ayak gibi eklemlerde oluşan progresif enflamatuar deformatif süreç beraberinde ağrı, hareket kısıtlılığı, fonksiyonel kısıtlanma gibi yaşam kalitesini de olumsuz etkileyen pek çok semptomun ortaya çıkmasına neden olmaktadır. Osteoartrit hastalarında fiziksel sorunların yanı sıra depresyon, anksiyete, umutsuzluk, sosyal izolasyon gibi pek çok psikososyal sorunlar da görülebilmektedir. Osteoartritin yönetimi, bu sorunların kapsamlı bir şekilde değerlendirilmesini, akut alevlenmelerin azaltılmasını, komplikasyonların önlenmesini ve ilerlemesini geciktirmeyi sağlayarak yaşam kalitesini optimize etmeye odaklanır. Bu amaçla hastalara uygun farmakolojik ve farmakolojik olmayan girişimleri uygulama ve öz yönetimlerinin desteklenmesi gerekmektedir. Bu nedenle, sağlık profesyonellerinden hemşirelerin osteoartrit hastasına bütüncül yaklaşması, hastaların yaşam kalitesi başta olmak üzere yaşamın tüm boyutlarında optimal iyilik halini sürdürmeye yönelik girişimleri önem arz etmektedir.
RESUME
L’arthrose (OA) est une maladie globale de toutes les structures d’une articulation. Elle est hétérogène par les différents phénotypes qui y sont associés. Si des contraintes biomécaniques aux multiples facteurs peuvent entraîner des lésions du cartilage, de la matrice extra-cellulaire et du chondrocyte, l’inactivité physique et surtout le mode de vie sédentaire représentent dans notre société des risques majeurs de développement de l’OA. En effet, le mode de vie sédentaire peut être responsable d’une atteinte infraclinique, précoce du cartilage du fait de l’inflexibilité métabolique et de l’insulino-résistance qu’elle entraîne, bien avant les complications métaboliques classiques de la sédentarité (obésité, maladies cardiovasculaires, dyslipidémies, diabète de type 2 et athérosclérose) qui vont entraîner un risque accru de mortalité au cours de l’arthrose. La prévention de l’OA non médicamenteuse repose non seulement sur la pratique d’activités physiques régulières mais aussi sur la réduction des périodes de sédentarité tout au long de la journée et le changement du comportement sédentaire.
Circadian clocks in the brain and peripheral tissues temporally coordinate local physiology to align with the 24 hours rhythmic environment through light/darkness, rest/activity and feeding/fasting cycles. Circadian disruptions (during ageing, shift work and jet-lag) have been proposed as a risk factor for degeneration and disease of tissues, including the musculoskeletal system. The intervertebral disc (IVD) in the spine separates the bony vertebrae and permits movement of the spinal column. IVD degeneration is highly prevalent among the ageing population and is a leading cause of lower back pain. The IVD is known to experience diurnal changes in loading patterns driven by the circadian rhythm in rest/activity cycles. In recent years, emerging evidence indicates the existence of molecular circadian clocks within the IVD, disruption to which accelerates tissue ageing and predispose animals to IVD degeneration. The cell-intrinsic circadian clocks in the IVD control key aspects of physiology and pathophysiology by rhythmically regulating the expression of ~3.5% of the IVD transcriptome, allowing cells to cope with the drastic biomechanical and chemical changes that occur throughout the day. Indeed, epidemiological studies on long-term shift workers have shown an increased incidence of lower back pain. In this review, we summarise recent findings of circadian rhythms in health and disease, with the IVD as an exemplar tissue system. We focus on rhythmic IVD functions and discuss implications of utilising biological timing mechanisms to improve tissue health and mitigate degeneration. These findings may have broader implications in chronic rheumatic conditions, given the recent findings of musculoskeletal circadian clocks.
Altering the food intake, exercise, and sleep patterns have a great influence on the homeostasis of the biological clock. This leads to accelerated aging of the articular cartilage, susceptibility to arthropathy and other aspects. Deficiency or overexpression of certain circadian clock‐related genes accelerates the cartilage deterioration and leads to phenotypic variation in different joints. The process of joint cartilage development includes the formation of joint site, interzone, joint cavitation, epiphyseal ossification center, and cartilage maturation. The mechanism by which, biological clock regulates the cell‐cycle, growth, metabolism, and other biological processes of chondrocytes is poorly understood. Here, we summarized the interaction between biological clock proteins and developmental pathways in chondrogenesis and provided the evidence from other tissues that further predicts the molecular patterns of these protein‐protein networks in activation, proliferation, and differentiation. The purpose of this review is to gain deeper understanding of the evolution of cartilage and its irreversibility seen in damage and aging.
Specific-pathogen free (SPF) animals were introduced into biomedical research in the early 1960s to reduce the incidence of disease into experimental design. The goal was to provide animals with selected microbiota compatible with sustained health. Sixty years later, SPF status has become a variable itself in biomedical research. Alterations in the gut microbiome-host relationship can profoundly influence basic physiology, immune/inflammatory function, susceptibility to infection and disease, and behavior. In addition, it can influence the translational success of a drug or technology from animal models to humans. We discuss this aspect of SPF status in animal models used for military or civilian trauma and shock research. Currently, there is a broad spectrum of SPF exclusion and inclusion criteria which vary from one supplier or animal husbandry facility. If translation to humans is the end-game of trauma research, we recommend replicating a gut microbiome similar to the wild-type for optimal success. We further suggest that at the end of each publication a URL access be provided on Animal Microbial/Pathogen Exclusion Status that a study was based upon. This may help address the differences in results within a single laboratory or between laboratories around the world and improve translation success.
Globally, a staggering 310 million major surgeries are performed each year; around 40 to 50 million in USA and 20 million in Europe. It is estimated that 1 to 4% of these patients will die, up to 15% will have serious postoperative morbidity, and 5 to 15% will be readmitted within 30 days. An annual global mortality of around 8 million patients places major surgery comparable with the leading causes of death from cardiovascular disease and stroke, cancer and injury. If surgical complications were classified as a pandemic, like HIV/AIDS or coronavirus (COVID-19), developed countries would work together and devise an immediate action plan and allocate resources to address it. Seeking to reduce preventable deaths and post-surgical complications would save billions of dollars in healthcare costs. Part of the global problem resides in differences in institutional practice patterns in high- and low-income countries, and part from a lack of effective perioperative drug therapies to protect the patient from surgical stress. We briefly review the history of surgical stress and provide a path forward from a systems-based approach. Key to progress is recognizing that the anesthetized brain is still physiologically ‘awake’ and responsive to the sterile stressors of surgery. New intravenous drug therapies are urgently required after anesthesia and before the first incision to prevent the brain from switching to sympathetic overdrive and activating secondary injury progression such as hyperinflammation, coagulopathy, immune activation and metabolic dysfunction. A systems-based approach targeting central nervous system-mitochondrial coupling may help drive research to improve outcomes following major surgery in civilian and military medicine.
Osteoarthritis (OA) is one of the most common chronic joint diseases. However, the mechanism remains unclear. The traditional renin-angiotensin system (RAS) is an important system for regulating homeostasis and controlling balance. In recent years, RAS-related components have played an important role in the occurrence of OA. The purpose of this review is to summarize the research results of RAS-related components that are associated with OA. This study systematically searched e-medical databases such as PubMed, Embase, Medline, and Web of Science. The search targets included English publications describing the effects of RAS-related components in OA, including the role of renin, angiotensin-converting enzyme (ACE), Angiotensin II (Ang II), and angiotensin receptor (ATR). Additionally, this study summarizes the potential pathways for RAS-related components to intervene in OA. This study found that RAS-related components including renin, ACE, Ang II, AT1R and AT2R are involved in inflammation and chondrocyte hypertrophy in OA. RAS is involved in signaling pathways including the NF-κB, JNK, VEGFR/Tie-2, and the Axna2/Axna2R axis ones, which may be potential targets for the treatment of OA. Although there are few studies on RAS in the field of OA, the pathogenic effect of RAS-related components is still an important topic in OA treatment, and great progress may be made in this aspect in future studies.
Objective:
In osteoarthritis (OA), articular chondrocytes manifest mitochondrial damage, including mitochondrial DNA 4977-bp (mtDNA4977) deletion that impairs mitochondrial function. OA chondrocytes have decreased activity of AMPK, an energy biosensor that promotes mitochondrial biogenesis. Here, we tested if pharmacologic AMPK activation, via downstream activation of predominately mitochondrially localized sirtuin 3 (SIRT3), reverses existing decreases in mtDNA integrity and function in human OA chondrocytes and limits mouse knee OA development.
Design:
We assessed mitochondrial DNA (mtDNA) integrity and function including the common mtDNA4977 deletion and mtDNA content, mitochondrial reactive oxygen species (mtROS) generation, oxygen consumption and intracellular ATP levels. Phosphorylation of AMPKα, expression and activity of SIRT3, acetylation and expression of the mitochondrial antioxidant enzyme SOD2 and DNA repair enzyme 8-oxoguanine glycosylase (OGG1), and expression of subunits of mitochondrial respiratory complexes were examined. We assessed effect of pharmacologic activation of AMPK on age-related spontaneous mouse knee OA.
Results:
The mtDNA4977 deletion was detected in both OA chondrocytes and menadione-treated normal chondrocytes, associated with increased mtROS, decreased SIRT3, and increased acetylation of SOD2 and OGG1. AMPKα1 deficient chondrocytes exhibited significantly reduced SIRT3 activity. AMPK pharmacologic activation attenuated existing mtDNA4977 deletion and improved mitochondrial functions in OA chondrocytes via SIRT3 by reducing acetylation and increasing expression of SOD2 and OGG1, and limited aging-associated mouse knee OA development and progression.
Conclusions:
AMPK activation, via SIRT3, limits oxidative stress and improves mitochondrial DNA integrity and function in OA chondrocytes. These effects likely contribute to chondroprotective effects of AMPK activity.
Exosomes are a subset of small, membrane-bound extracellular vesicles that are important for communication among cells. They originate from the cell membrane during endocytic internalization, and are stable in biological fluids, including blood and synovial fluids. Increasing knowledge is emerging about exosomes in joint diseases, including osteoarthritis, rheumatoid arthritis, osteonecrosis of the femoral head, and others. Exosomes in synovial fluid can lead to inflammation, degeneration of cartilage, and destruction of joints. Exosomes in blood have diagnostic value in the early disease stage or for complicated conditions of joint diseases. Exosomes from stem cells could delay diseases and repair joints. For a comprehensive understanding about the emerging role of exosomes in joint diseases, we introduced the isolation and verification of exosomes from synovial fluid, reviewed the physiological and pathological effects of exosomes on joints, and discussed the diagnostic value and therapeutic potential of exosomes in joint diseases. In the future, immunologically active exosomes and engineered exosomes will of interest in the joint diseases. Challenges in the field of exosomes in joint-disease research include complex and expensive isolation, detection of contributing molecular, effectiveness and safety evaluation. In summary, challenges remain, but the field of exosomes in joint diseases has potential, including in mechanisms, diagnoses and therapies.
Background:
Tranexamic acid (TXA) is commonly used in orthopedic surgery to reduce excessive bleeding and transfusion requirements. Our aim was to examine if TXA was required in all osteoarthritis patients undergoing TKA surgery, and its possible effects on systemic inflammation and coagulation properties.
Methods:
Twenty-three patients (Oxford Score 22-29) were recruited consecutively; 12 patients received TXA before (IV, 1.2 g/90 kg) and immediately after surgery (intra-articular, 1.4 g/90 kg). Inflammatory mediators and ROTEM parameters were measured in blood at baseline, after the first bone-cut, immediately after surgery, and postoperative days 1 and 2.
Results:
After the bone cut and surgery, TXA significantly increased MCP-1, TNF-α, IL-1β and IL-6 levels compared to non-TXA patients, which was further amplified postoperatively. During surgery, TXA significantly prolonged EXTEM clot times, indicating a thrombin-slowing effect, despite little or no change in clot amplitude or fibrinogen. TXA was associated with three- to fivefold increases in FIBTEM maximum lysis (ML), a finding counter to TXA's antifibrinolytic effect. Maximum lysis for extrinsic and intrinsic pathways was < 8%, indicating little or no hyperfibrinolysis. No significant differences were found in postoperative hemoglobin between the two groups.
Conclusions:
TXA was associated with increased systemic inflammation during surgery compared to non-TXA patients, with further amplification on postoperative days 1 and 2. On the basis of little or no change in viscoelastic clot strength, fibrinogen or clot lysis, there appeared to be no clinical justification for TXA in our group of patients. Larger prospective, randomized trials are required to investigate a possible proinflammatory effect in TKA patients.
Obesity is a risk factor for osteoarthritis (OA), the greatest cause of disability in the US. The impact of obesity on OA is driven by systemic inflammation, and increased systemic inflammation is now understood to be caused by gut microbiome dysbiosis. Oligofructose, a nondigestible prebiotic fiber, can restore a lean gut microbial community profile in the context of obesity, suggesting a potentially novel approach to treat the OA of obesity. Here, we report that - compared with the lean murine gut - obesity is associated with loss of beneficial Bifidobacteria, while key proinflammatory species gain in abundance. A downstream systemic inflammatory signature culminates with macrophage migration to the synovium and accelerated knee OA. Oligofructose supplementation restores the lean gut microbiome in obese mice, in part, by supporting key commensal microflora, particularly Bifidobacterium pseudolongum. This is associated with reduced inflammation in the colon, circulation, and knee and protection from OA. This observation of a gut microbiome-OA connection sets the stage for discovery of potentially new OA therapeutics involving strategic manipulation of specific microbial species inhabiting the intestinal space.
Cellular homeostasis is in part controlled by biological generated electrical activity. By interfacing biology with electronic devices this electrical activity can be modulated to actuate cellular behaviour. There are current limitations in merging electronics with biology sufficiently well to target and sense specific electrically active components of cells. By addressing this limitation, researchers give rise to new capabilities for facilitating the twoway transduction signalling mechanisms between the electronic and cellular components. This is required to allow significant advancement of bioelectronic technology which offers new ways of treating and diagnosing diseases. Most of the progress that has been achieved to date in developing bioelectronic therapeutics stimulate neural communication, which ultimately orchestrates organ function back to a healthy state. Some devices used in therapeutics include cochlear and retinal implants and vagus nerve stimulators. However, all cells can be effected by electrical inputs which gives rise to the opportunity to broaden the use of bioelectronic medicine for treating disease. Electronic actuation of non-excitable cells has been shown to lead to ‘programmed’ cell behaviour via application of electronic input which alter key biological processes. A neglected form of cellular electrical communication which has not yet been considered when developing bioelectronics therapeutics is faradaic currents. These are generated during redox reactions. A precedent of electrochemical technology being used to modulate these reactions thereby controlling cell behaviour has already been set. In this mini review we highlight the current state of the art of electronic routes to modulating cell behaviour and identify new ways in which electrochemistry could be used to contribute to the new field of bioelectronic medicine.
Introduction
Osteoarthritis (OA) is a heterogeneous and complex disease. We have used a network biology approach based on genome-wide analysis of gene expression in OA knee cartilage to seek evidence for pathogenic mechanisms that may distinguish different patient subgroups.
Methods
Results from RNA-Sequencing (RNA-Seq) were collected from intact knee cartilage at total knee replacement from 44 patients with OA, from 16 additional patients with OA and 10 control patients with non-OA. Results were analysed to identify patient subsets and compare major active pathways.
Results
The RNA-Seq results showed 2692 differentially expressed genes between OA and non-OA. Analysis by unsupervised clustering identified two distinct OA groups: Group A with 24 patients (55%) and Group B with 18 patients (41%). A 10 gene subgroup classifier was validated by RT-qPCR in 16 further patients with OA. Pathway analysis showed increased protein expression in both groups. PhenomeExpress analysis revealed group differences in complement activation, innate immune responses and altered Wnt and TGFβ signalling, but no activation of inflammatory cytokine expression. Both groups showed suppressed circadian regulators and whereas matrix changes in Group A were chondrogenic, in Group B they were non-chondrogenic with changes in mechanoreceptors, calcium signalling, ion channels and in cytoskeletal organisers. The gene expression changes predicted 478 potential biomarkers for detection in synovial fluid to distinguish patients from the two groups.
Conclusions
Two subgroups of knee OA were identified by network analysis of RNA-Seq data with evidence for the presence of two major pathogenic pathways. This has potential importance as a new basis for the stratification of patients with OA for drug trials and for the development of new targeted treatments.
Given the key role of butyrate for host health, understanding the ecology of intestinal butyrate-producing communities is a top priority for gut microbiota research. To this end, we performed a pooled analysis on 2,387 metagenomic/transcriptomic samples from 15 publicly available data sets that originated from three continents and encompassed eight diseases as well as specific interventions. For analyses, a gene catalogue was constructed from gene-targeted assemblies of all genes from butyrate synthesis pathways of all samples and from an updated reference database derived from genome screenings. We demonstrate that butyrate producers establish themselves within the first year of life and display high abundances (=20% of total bacterial community) in adults regardless of origin. Various bacteria form this functional group, exhibiting a biochemical diversity including different pathways and terminal enzymes, where one carbohydrate-fueled pathway was dominant with butyryl coenzyme A (CoA):acetate CoA transferase as the main terminal enzyme. Subjects displayed a high richness of butyrate producers, and 17 taxa, primarily members of the Lachnospiraceae and Ruminococcaceae along with some Bacteroidetes, were detected in >70% of individuals, encompassing ~85% of the total butyrate-producing potential. Most of these key taxa were also found to express genes for butyrate formation, indicating that butyrate producers occupy various niches in the gut ecosystem, concurrently synthesizing that compound. Furthermore, results from longitudinal analyses propose that diversity supports functional stability during ordinary life disturbances and during interventions such as antibiotic treatment. A reduction of the butyrate-producing potential along with community alterations was detected in various diseases, where patients suffering from cardiometabolic disorders were particularly affected.
Significance
Knee osteoarthritis is a highly prevalent, disabling joint disease with causes that remain poorly understood but are commonly attributed to aging and obesity. To gain insight into the etiology of knee osteoarthritis, this study traces long-term trends in the disease in the United States using large skeletal samples spanning from prehistoric times to the present. We show that knee osteoarthritis long existed at low frequencies, but since the mid-20th century, the disease has doubled in prevalence. Our analyses contradict the view that the recent surge in knee osteoarthritis occurred simply because people live longer and are more commonly obese. Instead, our results highlight the need to study additional, likely preventable risk factors that have become ubiquitous within the last half-century.
Purpose of the review:
Osteoarthritis (OA) is a chronic, painful joint disease that affects approximately 40% of adults over 70 year. Age is the strongest predictor of OA, while obesity is considered the primary preventable risk factor for OA. Both conditions are associated with abnormal innate immune inflammatory responses that contribute to OA progression and are the focus of this review.
Recent findings:
Recent studies have identified risk factors for OA progression including increased innate immune responses secondary to aging-associated myeloid skewing, obesity-related myeloid activation, and synovial tissue hyperplasia with activated macrophage infiltration. Toll-like receptor (TLR)4-induced catabolic responses also play a significant role in OA. The complex interplay between obesity and aging-associated macrophage activation, pro-inflammatory cytokine production from TLR-driven responses, and adipokines leads to a vicious cycle of synovial hyperplasia, macrophage activation, cartilage catabolism, infrapatellar fat pad fibrosis, and joint destruction.
The pathogenesis of osteoarthritis (OA) is poorly understood, and therapeutic approaches are limited to preventing progression of the disease. Recent studies have shown that exosomes play a vital role in cell-to-cell communication, and pathogenesis of many age-related diseases. Molecular profiling of synovial fluid derived exosomal miRNAs may increase our understanding of OA progression and may lead to the discovery of novel biomarkers and therapeutic targets. In this article we report the first characterization of exosomes miRNAs from human synovial fluid. The synovial fluid exosomes share similar characteristics (size, surface marker, miRNA content) with previously described exosomes in other body fluids. MiRNA microarray analysis showed OA specific exosomal miRNA of male and female OA. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified gender-specific target genes/signaling pathways. These pathway analyses showed that female OA specific miRNAs are estrogen responsive and target TLR (toll-like receptor) signaling pathways. Furthermore, articular chondrocytes treated with OA derived extracellular vesicles had decreased expression of anabolic genes and elevated expression of catabolic and inflammatory genes. In conclusion, synovial fluid exosomal miRNA content is altered in patients with OA and these changes are gender specific.
The importance of the nociceptive nervous system for maintaining tissue homeostasis
has been known for some time, and it has also been suggested that organogenesis and tissue
repair are under neuronal control. Changes in peripheral joint innervation are supposed to be
partly responsible for degenerative alterations in joint tissues which contribute to development of
osteoarthritis. Various resident cell types of the musculoskeletal system express receptors for sensory
and sympathetic neurotransmitters, allowing response to peripheral neuronal stimuli. Among them
are mesenchymal stem cells, synovial fibroblasts, bone cells and chondrocytes of different origin,
which express distinct subtypes of adrenoceptors (AR), receptors for vasoactive intestinal peptide
(VIP), substance P (SP) and calcitonin gene-related peptide (CGRP). Some of these cell types synthesize
and secrete neuropeptides such as SP, and they are positive for tyrosine-hydroxylase (TH), the rate
limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters are
involved in the pathology of inflammatory diseases such as rheumatoid arthritis (RA) which manifests
mainly in the joints. In addition, they seem to play a role in pathogenesis of priori degenerative
joint disorders such as osteoarthritis (OA). Altogether it is evident that sensory and sympathetic
neurotransmitters have crucial trophic effects which are critical for joint tissue and bone homeostasis.
They modulate articular cartilage, subchondral bone and synovial tissue properties in physiological
and pathophysiological conditions, in addition to their classical neurological features.
Objectives:
Circadian rhythm (CR) was identified by RNA sequencing as the most dysregulated pathway in human osteoarthritis (OA) in articular cartilage. This study examined circadian rhythmicity in cultured chondrocytes and the role of the CR genes NR1D1 and BMAL1 in regulating chondrocyte functions.
Methods:
RNA was extracted from normal and OA-affected human knee cartilage (n=14 each). Expression levels of NR1D1 and BMAL1 mRNA and protein were assessed by quantitative PCR and immunohistochemistry. Human chondrocytes were synchronized and harvested at regular intervals to examine circadian rhythmicity in RNA and protein expression. Chondrocytes were treated with small interfering RNA (siRNA) for NR1D1 or BMAL1, followed by RNA sequencing and analysis of the effects on the TGF-β pathway.
Results:
NR1D1 and BMAL1 mRNA and protein levels were significantly reduced in OA compared to normal cartilage. In cultured human chondrocytes, a clear circadian rhythmicity was observed for NR1D1 and BMAL1. Increased BMAL1 expression was observed after knocking down NR1D1, and decreased NR1D1 levels were observed after knocking down BMAL1. Sequencing of RNA from chondrocytes treated with NR1D1 or BMAL1 siRNA identified 330 and 68 significantly different genes, respectively, and this predominantly affected the TGF-β signaling pathway.
Conclusions:
The circadian rhythm pathway is dysregulated in OA cartilage. Interference with circadian rhythmicity in cultured chondrocytes affects TGF-β signaling, which is a central pathway in cartilage homeostasis.
Purpose of review:
Inflammatory changes in joint tissues can be detected by modern imaging techniques in osteoarthritis patients, but may be clinically subtle compared with many other types of arthritis. These changes associate with disease progression and clinical severity, and many inflammatory mediators may have biomarker utility. Moreover, a number of inflammatory mechanisms play a role in animal models of disease, but it is still not clear which mechanisms predominate and might be therapeutically manipulated most effectively. This review highlights specific examples of recent advances published in the past 18 months that have advanced this field.
Recent findings:
Clinical investigators now show that synovial inflammation is associated with pain sensitization, and similar to knee osteoarthritis, is a common and important feature of hand osteoarthritis. In addition, recent advances in basic studies demonstrate inflammatory markers and mechanisms related to leukocyte activity, innate immune mechanisms, and the chondrocyte-intrinsic inflammatory response that might provide better opportunities for early detection, prognosis, or therapeutic intervention.
Summary:
Inflammation plays a central role in osteoarthritis pathogenesis, but additional translational work in this field is necessary, as are more clinical trials of anti-inflammatory approaches.
Osteoarthritis (OA) is the most common joint disorder, is associated with an increasing socioeconomic impact owing to the ageing population and mainly affects the diarthrodial joints. Primary OA results from a combination of risk factors, with increasing age and obesity being the most prominent. The concept of the pathophysiology is still evolving, from being viewed as cartilage-limited to a multifactorial disease that affects the whole joint. An intricate relationship between local and systemic factors modulates its clinical and structural presentations, leading to a common final pathway of joint destruction. Pharmacological treatments are mostly related to relief of symptoms and there is no disease-modifying OA drug (that is, treatment that will reduce symptoms in addition to slowing or stopping the disease progression) yet approved by the regulatory agencies. Identifying phenotypes of patients will enable the detection of the disease in its early stages as well as distinguish individuals who are at higher risk of progression, which in turn could be used to guide clinical decision making and allow more effective and specific therapeutic interventions to be designed. This Primer is an update on the progress made in the field of OA epidemiology, quality of life, pathophysiological mechanisms, diagnosis, screening, prevention and disease management.
Osteoarthritis (OA) is a prevalent, disabling disorder of the joints that affects a large population worldwide and for which there is no definitive cure. This review provides critical insights into the basic knowledge on OA that may lead to innovative end efficient new therapeutic regimens. While degradation of the articular cartilage is the hallmark of OA, with altered interactions between chondrocytes and compounds of the extracellular matrix, the subchondral bone has been also described as a key component of the disease, involving specific pathomechanisms controlling its initiation and progression. The identification of such events (and thus of possible targets for therapy) has been made possible by the availability of a number of animal models that aim at reproducing the human pathology, in particular large models of high tibial osteotomy (HTO). From a therapeutic point of view, mesenchymal stem cells (MSCs) represent a promising option for the treatment of OA and may be used concomitantly with functional substitutes integrating scaffolds and drugs/growth factors in tissue engineering setups. Altogether, these advances in the fundamental and experimental knowledge on OA may allow for the generation of improved, adapted therapeutic regimens to treat human OA.
This paper focuses on the relationship between the circadian system and glucose metabolism. Research across the translational spectrum confirms the importance of the circadian system for glucose metabolism and offers promising clues as to when and why these systems go awry. In particular, basic research has started to clarify the molecular and genetic mechanisms through which the circadian system regulates metabolism. The study of human behavior, especially in the context of psychiatric disorders, such as bipolar disorder and major depression, forces us to see how inextricably linked mental health and metabolic health are. We also emphasize the remarkable opportunities for advancing circadian science through big data and advanced analytics. Advances in circadian research have translated into environmental and pharmacological interventions with tremendous therapeutic potential.
Background:
We conducted an exploratory analysis of osteoarthritis progression among medication users in the Osteoarthritis Initiative to identify interventions or pathways that may be associated with disease modification and therefore of interest for future clinical trials.
Methods:
We used participants from the Osteoarthritis Initiative with annual medication inventory data between the baseline and 36-month follow-up visit (n = 2938). Consistent medication users were defined for each medication classification as a participant reporting at all four annual visits that they were regularly using an oral prescription medication at the time of the visit. The exploratory analysis focused on medication classes with 40 or more users. The primary outcome measures were medial tibiofemoral joint space width change and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) knee pain score change (12-36-month visits). Within each knee, we explored eight comparisons between users and matched or unmatched nonusers (defined two ways). An effect size of each comparison was calculated. Medication classes had potential signals if (a) both knees had less progression among users compared with nonusers, or (b) there was less progression based on structure and symptoms in one knee.
Results:
We screened 28 medication classes. Six medication classes had signals for fewer structural changes and better knee pain changes: alpha-adrenergic blockers, antilipemic (excluding statins and fibric acid), anticoagulants, selective serotonin reuptake inhibitors, antihistamines, and antineoplastic agents. Four medication classes had signals for structural changes alone: anti-estrogen (median effect size = 0.28; range = -0.41-0.64), angiotensin-converting enzyme inhibitors (median effect size = 0.13; range = -0.08-0.28), beta-adrenergic blockers (median effect size = 0.09; range = 0.01-0.30), and thyroid agents (median effect size = 0.04; range = -0.05-0.14). Thiazide diuretics had evidence for symptom modification (median effect size = -0.12; range = -0.24-0.04).
Conclusions:
Users of neurovascular, antilipemic, or hormonal interventions may have less disease progression compared with nonusers.
Intestinal microbiota is highly involved in host physiology and pathology through activity of the microbiome and its metabolic products. Osteoarthritis (OA) is a common form of arthritis characterized by articular cartilage destruction and osteophyte formation. Although various person-level risk factors, such as age, sex, and obesity, have been proposed for the pathogenesis of OA, the underlying links between these person-level factors and OA are still enigmatic. Based on the current understanding in the crosstalk between intestinal microbiota and these risk factors, intestinal microbiota could be considered as a major hidden risk factor that provides a unifying mechanism to explain the involvement of these person-level risk factors in OA.
There is strong diurnal variation in the symptoms and severity of chronic inflammatory diseases, such as rheumatoid arthritis. In addition, disruption of the circadian clock is an aggravating factor associated with a range of human inflammatory diseases. To investigate mechanistic links between the biological clock and pathways underlying inflammatory arthritis, mice were administered collagen (or saline as a control) to induce arthritis. The treatment provoked an inflammatory response within the limbs, which showed robust daily variation in paw swelling and inflammatory cytokine expression. Inflammatory markers were significantly repressed during the dark phase. Further work demonstrated an active molecular clock within the inflamed limbs and highlighted the resident inflammatory cells, fibroblast-like synoviocytes (FLSs), as a potential source of the rhythmic inflammatory signal. Exposure of mice to constant light disrupted the clock in peripheral tissues, causing loss of the nighttime repression of local inflammation. Finally, the results show that the core clock proteins CRYPTOCHROMES 1 and 2 repressed inflammation within the FLSs, and provide novel evidence that a CRYPTOCHROME activator has anti-inflammatory properties in human cells. We conclude that under chronic inflammatory conditions, the clock actively represses inflammatory pathways during the dark phase. This interaction has exciting potential as a therapeutic avenue for treatment of inflammatory disease.-Hand, L. E., Hopwood, T. W., Dickson, S. H., Walker, A. L., Loudon, A. S. I., Ray D. W., Bechtold, D. A., Gibbs, J. E. The circadian clock regulates inflammatory arthritis.
Osteoarthritis (OA) is the most prevalent and debilitating joint disease, and there are currently no effective disease-modifying treatments available. Multiple risk factors for OA, such as aging, result in progressive damage and loss of articular cartilage. Autonomous circadian clocks have been identified in mouse cartilage, and environmental disruption of circadian rhythms in mice predisposes animals to OA-like damage. However, the contribution of the cartilage clock mechanisms to the maintenance of tissue homeostasis is still unclear. Here, we have shown that expression of the core clock transcription factor BMAL1 is disrupted in human OA cartilage and in aged mouse cartilage. Furthermore, targeted Bmal1 ablation in mouse chondrocytes abolished their circadian rhythm and caused progressive degeneration of articular cartilage. We determined that BMAL1 directs the circadian expression of many genes implicated in cartilage homeostasis, including those involved in catabolic, anabolic, and apoptotic pathways. Loss of BMAL1 reduced the levels of phosphorylated SMAD2/3 (p-SMAD2/3) and NFATC2 and decreased expression of the major matrix-related genes Sox9, Acan, and Col2a1, but increased p-SMAD1/5 levels. Together, these results define a regulatory mechanism that links chondrocyte BMAL1 to the maintenance and repair of cartilage and suggest that circadian rhythm disruption is a risk factor for joint diseases such as OA.
Articular cartilage degeneration is hallmark of osteoarthritis (OA). Low-grade chronic inflammation in the joint can promote OA progression. Emerging evidence indicates that bioenergy sensors couple metabolism with inflammation to switch physiological and clinical phenotypes. Changes in cellular bioenergy metabolism can reprogram inflammatory responses, and inflammation can disturb cellular energy balance and increase cell stress. AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) are two critical bioenergy sensors that regulate energy balance at both cellular and whole-body levels. Dysregulation of AMPK and SIRT1 has been implicated in diverse human diseases and aging. This review reveals recent findings on the role of AMPK and SIRT1 in joint tissue homeostasis and OA, with a focus on how AMPK and SIRT1 in articular chondrocytes modulate intracellular energy metabolism during stress responses (e.g., inflammatory responses) and how these changes dictate specific effector functions, and discusses translational significance of AMPK and SIRT1 as new therapeutic targets for OA.
Despite a technically perfect procedure, surgical stress can determine the success or failure of an operation. Surgical trauma is often referred to as the “neglected step-child” of global health in terms of patient numbers, mortality, morbidity and costs. A staggering 234 million major surgeries are performed every year, and depending upon country and institution, up to 4% of patients will die before leaving hospital, up to 15% will have serious post-operative morbidity, and 5 to 15% will be readmitted within 30 days. These percentages equate to around 1000 deaths and 4000 major complications every hour, and it has been estimated that 50% may be preventable. New frontline drugs are urgently required to make major surgery safer for the patient and more predictable for the surgeon. We review the basic physiology of the stress response from neuroendocrine to genomic systems, and discuss the paucity of clinical data supporting the use of statins, beta-adrenergic blockers and calcium channel blockers. Since cardiac-related complications are the most common, particularly in the elderly, a key strategy would be to improve ventricular-arterial coupling to safeguard the endothelium and maintain tissue oxygenation. Reduced O2 supply is associated with glycocalyx shedding, decreased endothelial barrier function, fluid leakage, inflammation and coagulopathy. A healthy endothelium may prevent these “secondary hit” complications, including possibly immunosuppression. Thus the four pillars of whole body resynchronization during surgical trauma, and targets for new therapies, are: 1) the CNS, 2) the heart, 3) arterial supply and venous return functions, and 4) the endothelium. This is termed the Central-Cardio-Vascular-Endothelium (CCVE) coupling hypothesis. Since similar sterile injury cascades exist in critical illness, accidental trauma, hemorrhage, cardiac arrest, infection and burns, new drugs that improve CCVE coupling may find wide utility in civilian and military medicine.
Circadian rhythms are 24h oscillations in physiology and behavior which allow organisms to anticipate and adapt to daily demands associated with the day/night cycle. The currently accepted model of the molecular clockwork is described as a transcriptional process composed of negative regulatory feedback loops. However, ample evidence underlines the important contribution of non-transcriptional and metabolic oscillations to cellular timekeeping. We summarize recent evidence pointing to the relationship between the transcriptional oscillator and metabolic redox state, with particular emphasis on the potential nodes of interaction. We highlight the intrinsic difficulty in segregating these two tightly coupled and interdependent processes, in living systems, and how disruption of their synchronicity impacts upon (patho)physiological processes as diverse as cardiovascular and metabolic disorders, aging, and cancer.
Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.
Cross-talk between the sympathetic nervous system (SNS) and immune system is vital for health and well-being. Infection, tissue injury and inflammation raise firing rates of sympathetic nerves, increasing their release of norepinephrine (NE) in lymphoid organs and tissues. NE stimulation of β2-adrenergic receptors (ARs) in immune cells activates the cAMP-protein kinase A (PKA) intracellular signaling pathway, a pathway that interfaces with other signaling pathways that regulate proliferation, differentiation, maturation and effector functions in immune cells. Immune-SNS cross-talk is required to maintain homeostasis under normal conditions, to develop an immune response of appropriate magnitude after injury or immune challenge, and subsequently restore homeostasis. Typically, β2-AR-induced cAMP is immunosuppressive. However, many studies report actions of β2-AR stimulation in immune cells that are inconsistent with typical cAMP-PKA signal transduction. Research during the last decade in non-immune organs, has unveiled novel alternative signaling mechanisms induced by β2-AR activation, such as a signaling switch from cAMP-PKA to mitogen-activated protein kinase (MAPK) pathways. If alternative signaling occurs in immune cells, it may explain inconsistent findings of sympathetic regulation of immune function. Here, we review β2-AR signaling, assess the available evidence for alternative signaling in immune cells, and provide insight into the circumstances necessary for "signal switching" in immune cells.
Over the past decades evidence has accumulated clearly demonstrating a pivotal role for the sympathetic nervous system (SNS) and its neurotransmitters in regulating inflammation. The first part of this review provides the reader with an overview showing that the interaction of the SNS with the immune system to control inflammation is strongly context-dependent (for example, depending on the activation state of the immune cell or neuro-transmitter concentration). In the second part we focus on autoimmune arthritis as a well investigated example for sympathetically controlled inflammation to show that the SNS and catecholamines play a differential role depending on the time point of ongoing disease. A model will be developed to explain the proinflammatory effects of the SNS in the early phase and the anti-inflammatory effects of catecholamines in the later phase of autoimmune arthritis. In the final part, a conceptual framework is discussed that shows that a major purpose of increased SNS activity is nourishment of a continuously activated immune system at a systemic level using energy-rich fuels (glucose, amino acids, lipids), while uncoupling from central nervous regulation occurs at sites of inflammation by repulsion of sympathetic fibers and local adrenoceptor regulation. This creates zones of ‘permitted local inflammation’. However, if this ‘inflammatory configuration’ persists and is strong, as in autoimmunity, the effects are detrimental because of the resultant chronic catabolic state, leading to cachexia, high blood pressure, insulin resistance, and increased cardiovascular mortality, and so on. Today, the challenge is to translate this conceptual knowledge into clinical benefit.
Introduction
Osteoarthritis (OA) is a whole joint disease, and characterized by progressive degradation of articular cartilage, synovial hyperplasia, bone remodeling and angiogenesis in various joint tissues. Exosomes are a type of microvesicles (MVs) that may play a role in tissue-tissue and cell-cell communication in homeostasis and diseases. We hypothesized that exosomes function in a novel regulatory network that contributes to OA pathogenesis and examined the function of exosomes in communication among joint tissue cells.
Methods
Human synovial fibroblasts (SFB) and articular chondrocytes were obtained from normal knee joints. Exosomes isolated from conditioned medium of SFB were analyzed for size, numbers, markers and function. Normal articular chondrocytes were treated with exosomes from SFB, and Interleukin-1β (IL-1β) stimulated SFB. OA-related genes expression was quantified using real-time PCR. To analyze exosome effects on cartilage tissue, we performed glycosaminoglycan release assay. Angiogenic activity of these exosomes was tested in migration and tube formation assays. Cytokines and miRNAs in exosomes were analyzed by Bio-Plex multiplex assay and NanoString analysis.
Results
Exosomes from IL-1β stimulated SFB significantly up-regulated MMP-13 and ADAMTS-5 expression in articular chondrocytes, and down-regulated COL2A1 and ACAN compared with SFB derived exosomes. Migration and tube formation activity were significantly higher in human umbilical vein endothelial cells (HUVECs) treated with the exosomes from IL-1β stimulated SFB, which also induced significantly more proteoglycan release from cartilage explants. Inflammatory cytokines, IL-6, MMP-3 and VEGF in exosomes were only detectable at low level. IL-1β, TNFα MMP-9 and MMP-13 were not detectable in exosomes. NanoString analysis showed that levels of 50 miRNAs were differentially expressed in exosomes from IL-1β stimulated SFB compared to non-stimulated SFB.
Conclusions
Exosomes from IL-1β stimulated SFB induce OA-like changes both in vitro and in ex vivo models. Exosomes represent a novel mechanism by which pathogenic signals are communicated among different cell types in OA-affected joints.
The prevalence of osteoarthritis (OA) is rising for reasons that are not fully understood. In this Opinion article, we review the possibility that OA is an evolutionary mismatch disease, which is a disease more common today than in the past because genes inherited from previous generations are inadequately or imperfectly adapted to modern environmental conditions. We focus on four major environmental factors in OA pathogenesis that have become ubiquitous within the past half-century: obesity, metabolic syndrome, dietary changes and physical inactivity. Because a cure for OA does not yet exist, prevention strategies that target these modifiable environmental factors are needed to curb further increases in OA prevalence.
The history of osteoarthritis (OA) is important because it can help broaden our perspective on past and present controversies. The naming of OA, beginning with Heberden's nodes, is itself a fascinating story. According to Albert Hoffa, R. Llewellyn Jones and Archibald Edward Garrod, the name OA was introduced in the mid-19th century by surgeon Richard von Volkmann who distinguished it from rheumatoid arthritis and gout. Others preferred the terms 'chronical rheumatism', 'senile arthritis', 'hypertrophic arthritis' or 'arthritis deformans'. A similar narrative applies to the concept of OA affecting the whole joint vs. the 'wear-and-tear' hypothesis, inflammation and the role of the central nervous system (CNS). In the late 19th and early 20th centuries, the Garrods (father and son) and Hermann Senator argued that OA was a whole joint disease, and that inflammation played a major role in its progression. Garrod Jnr and John Spender also linked OA to a neurogenic lesion 'outside the joint'. The remaining 20th century was no less dynamic, with major advances in basic science, diagnostics, treatments, surgical interventions and technologies. Today, OA is characterized as a multi-disease with inflammation, immune and CNS dysfunction playing central roles in whole joint damage, injury progression, pain and disability. In the current 'omics' era (genomics, proteomics and metabolomics), we owe a great debt to past physicians and surgeons who dared to think 'outside-the-box' to explain and treat OA. Over 130 years later, despite these developments, we still don't fully understand the unravelling complexities of OA, and we still don't have a cure.
Objective:
(i) To determine the association between the presence of comorbidities and severity of pain and physical dysfunction in people with knee and/or hip osteoarthritis; (ii) to explore associations between specific comorbidities (cardiac disease and/or hypertension, diabetes, depression, and back pain) and symptom severity.
Methods:
Studies were identified through systematic searches in four electronic databases and grey literature, and, subsequently, methodologically appraised. Eligible citations entailed cross-sectional or longitudinal studies as well as randomised controlled trials providing data of a direct association between comorbidity presence and the severity of self-reported and/or performance-based symptoms of pain and/or physical functioning, in people with knee and/or hip osteoarthritis. We performed random-effects meta-analysis if at least two citations of low-to-moderate risk of bias were available. The quality of the body of evidence was determined using Cochrane-recommended methods.
Results:
Of all eligible citations (n = 26), 17 studies were entered in meta-analysis. Moderate quality evidence revealed an association between having ≥1 general comorbidity and worsening of pain (regression coefficient (95% confidence interval (CI)): 0.18 (95% CI: 0.14,0.22)) and/or performance-based physical functioning (0.20 (95% CI: 0.10,0.29)). The presence of cardiac disease and/or hypertension (self-reported: 0.08 (95% CI: 0.01,0.16); performance-based: 0.11 (95% CI: 0.02,0.20)), or back pain (self-reported: 0.12 (95% CI: 0.04,0.20)) predicted deteriorated physical functioning. Co-existing diabetes was associated with worse pain (0.10 (95% CI: 0.02,0.17)). Other findings were non-significant and/or the evidence of poor quality.
Conclusions:
Greater comorbidity burden contributes to worse pain and performance-based physical function in people with knee and/or hip osteoarthritis. Suffering comorbid cardiac disease including hypertension, back pain or diabetes may have differential effects on symptom severity.
Sequelae frequently seen in patients with chronic inflammatory diseases, such as fatigue, depressed mood, sleep alterations, loss of appetite, muscle wasting, cachectic obesity, bone loss and hypertension, can be the result of energy shortages caused by an overactive immune system. These sequelae can also be found in patients with chronic inflammatory diseases that are in remission and in ageing individuals, despite the immune system being less active in these situations. This Perspectives article proposes a new way of understanding situations of chronic inflammation (such as rheumatic diseases) and ageing based on the principles of evolutionary medicine, energy regulation and neuroendocrine–immune crosstalk. A conceptual framework is provided to enable physicians and scientists to better understand the signs and symptoms of chronic inflammatory diseases and long-term disease consequences resulting from physical and mental inactivity.
The mammalian circadian clock system, which includes the master clock and peripheral clocks, times different biological processes in reaction to external cues, such as the light-dark cycle. However, the chronobiology of prokaryotic cells is less well understood, except for in cyanobacteria. The recent blooming of gut microbiome research has revealed a critical role for the trillions of microbes residing in the vertebrate gut in determining both health and disease in the host. The question of whether the gut microbiome exhibits circadian oscillation and how it synchronizes with the host circadian clock has attracted considerable interest. In this review, we discuss the time-of-day–dependent compositional and functional structure within the gut microbial community, how it is regulated by the host, and how it reciprocally influences the host circadian clock.
Imbalance in the autonomic nervous system (ANS) has been observed in many established chronic autoimmune diseases, including rheumatoid arthritis (RA), which is a prototypic immune-mediated inflammatory disease (IMID). We recently discovered that autonomic dysfunction precedes and predicts arthritis development in subjects at risk of developing seropositive RA. In addition, RA patients with relatively high vagus nerve tone (higher parasympathetic parameters, measured by heart rate variability) respond better to antirheumatic therapies. Together, these data suggest that the ANS may control inflammation in humans. This notion is supported by experimental studies in animal models of RA. We have found that stimulation of the so-called cholinergic anti-inflammatory pathway by efferent electrical vagus nerve stimulation (VNS) or pharmacological activation of the alpha7 subunit of nicotinic acetylcholine receptors (α7nAChR) improves clinical signs and symptoms of arthritis, reduces cytokine production and protects against progressive joint destruction. Conversely, increased arthritis activity was observed in alpha7nAChR knockout mice. These studies together with previous work in animal models of sepsis and other forms of inflammation provided the rationale for an experimental clinical trial in patients with RA. We could for the first time show that an implantable vagus nerve stimulator inhibits peripheral blood cytokine production in humans. VNS significantly inhibited TNF and IL-6 production and improved RA disease severity, even in some patients with therapy-resistant disease. This work strongly supports further studies using a bioelectronic approach to treat RA and other IMIDs.
Metabolism has a key role in the physiological turnover of synovial joint tissues, including articular cartilage
In osteoarthritis (OA), chondrocytes and cells in joint tissues other than cartilage undergo metabolic alterations and shift from a resting regulatory state to a highly metabolically active state
Inflammatory mediators, metabolic intermediates and immune cells influence cellular responses in the pathophysiology of OA
Key metabolic pathways and mediators might be targets of future therapies for OA
Background:
Although osteoarthritis has predominantly been considered a non-inflammatory degenerative arthropathy, there is growing evidence that various inflammatory and immunological processes might contribute to the onset, progression, and burden of the disease.
Objective:
The purpose of the present investigation was to study the systemic inflammatory and stress responses and the innate response mediated by neutrophils in OA patients.
Method:
A group of patients diagnosed with primary OA according to the American College of Rheumatology criteria and a control group of age-matched healthy volunteers were enrolled in the study. Serum inflammatory cytokine levels (IL-1β, TNF-α, IL-8, IL-6, IL-10, and TGF-β) were evaluated using the Bio-Plex Luminex system. Circulating neuroendocrine-stress biomarkers, such as cortisol and extracellular 72 kDa heat shock protein, were measured by ELISA. The phagocytic and microbicide capacities of circulating neutrophils were evaluated by flow cytometry. All parameters were determined in all volunteers.
Results:
The OA patients showed an inflammatory state accompanied by an altered stress response. This was manifest in high circulating levels of the inflammatory cytokines IL-1β, TNF-α, IL-8, IL-6, and TGF-β and the stress protein eHsp72. There were also decreased systemic levels of cortisol, and a reduction in neutrophil phagocytic and microbicidal capacities.
Conclusion:
An immune-neuroendocrine dysregulation affecting both systemic inflammatory and stress mediators and the function of innate immune cells underlies OA. This reflects an altered feedback between the innate/inflammatory and stress responses in this pathology.
Objectives:
To determine if 1) Osteoarthritis (OA)-related pain is associated with the diurnal cortisol pattern and cortisol levels; 2) the diurnal pattern of cortisol varies with severity of OA pain and 3) the association between OA pain and cortisol is mediated by daily experience variables (DEV).
Design:
In a community-based study of changes in regional and widespread pain among women with OA, participants (n=31) completed daily diaries and collected three saliva samples daily for 7 days. Severity of OA-related pain was assessed by the validated Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale. Multilevel regression analyses estimated associations between OA pain and diurnal cortisol levels and slopes, controlling for body mass index, medication use, time and day. Mediation analyses examined DEV as potential mediators of the association between OA pain and cortisol.
Results:
The mean age was 57 years and average BMI 31kg/m(2). Mean WOMAC pain subscale score was 8.8. Women with higher WOMAC pain scores had higher cortisol throughout the day. The estimated association of WOMAC with cortisol [ß 0.083(0.02, 0.15) p =0.009] represents a ∼ 9% increase in cortisol for every unit increase in WOMAC pain score. Women with WOMAC pain scores > 9 had higher cortisol levels than those with scores <9. Examination of DEV revealed no significant mediated associations between these relationships at the daily level.
Conclusion:
In women with OA, disease-related pain is positively associated with cortisol production, particularly with greater pain severity. Future studies should explore biologic mediating variables between OA pain and cortisol.
Osteoarthritis (OA) is a prevalent and debilitating joint disease for which ageing, obesity and chronic inflammation are known risk factors. The central, peripheral and autonomic nervous systems are essential in all metabolic systems, and emerging evidence suggests a role for these systems in OA. In the past few years, metabolic diseases, such as obesity or diabetes, have been linked to disruption of circadian rhythms that are tightly regulated by the nervous system, whereas inflammatory and autoimmune diseases are known to be linked to disruption of the cholinergic vagus nerve reflex. Interestingly, metabolism, inflammation and circadian rhythms have all been linked to the development and progression of OA. This article reviews current knowledge of the direct and indirect roles of the nervous system and circadian system in the initiation and/or progression of OA, and highlights the directions for future research in this emerging field.
Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside. Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice-like newborn, but not adult, humans-lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.
This narrative review updates the recent advances in our understanding of the multifactorial pathogenesis for reduced postdischarge physical and cognitive function after fast-track surgery, using total hip and knee arthroplasty as surgical models. Relevant factors discussed include the surgical stress responses and potential methods for controlling postsurgical inflammation, pain, and cognitive dysfunction. The continuation of moderate to severe pain in up to 30% of patients for 2-4 weeks calls for better understanding of the underlying mechanisms and development of effective multimodal opioid-sparing analgesic regimens. The need for the development of effective physiotherapy programmes on a patient-specific basis is discussed, along with the need for optimal assessment of postoperative function to guide rehabilitation. Other relevant factors discussed include the role of orthostatic intolerance, sleep disturbances, and blood management, and specific patient populations at risk for adverse outcomes, including psychiatric disorders, to identify and guide future interventions for optimizing functional postdischarge outcomes after fast-track surgery.
© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Obesity is associated with an increased risk of developing osteoarthritis (OA), even in non-weight bearing joints. High levels of adipose tissue-associated inflammation may explain this association.
Published evidence looking at the associations between components of Metabolic Syndrome (MetS) and knee, hip or hand OA and the higher mortality described with knee OA.
Development of MetS and OA shares a relationship with adipose tissue-associated inflammation. This review supports this inflammatory pathway being part of the shared mechanism behind obesity as a risk factor for OA and the recently described OA-associated increased mortality.
In an era of an obesity epidemic, this review identifies a need for well-designed cohort studies assessing early metabolic changes in populations at high risk of OA and MetS, and to identify risk factors for increased mortality in patients with OA.
© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Objective: To explore potential associations between proinflammatory cytokines in synovial fluid and progression of OA in meniscectomized subjects.
Design: We studied 132 subjects on average 18 years after meniscectomy, with a second examination 4-10 years later. We measured concentrations of interleukin (IL)-6, -8 and tumor necrosis factor (TNF)-α by multiplex immunoassay, graded radiographic features of tibiofemoral and patellofemoral OA according to the Osteoarthritis Research Society International (OARSI) atlas, scored patient-reported outcomes using the Knee Injury and Osteoarthritis Outcome Score (KOOS), and used logistic regression (adjusted for age, gender, body mass index, and time between examinations) for assessment of associations.
Results: Higher first examination concentrations of IL-6 and TNF-α were associated with increased risk for subsequent osteophyte progression (odds ratios (OR); 95% confidence intervals 1.05; 1.00 to 1.09 and 1.35; 1.03 to 1.75). Higher second examination concentrations of TNF-α were associated with having progressed in loss of joint space (OR 1.70; 1.15 to 2.52) or having worsened in the activity of daily living subscale of KOOS (OR 1.50; 1.07 to 2.09) in the preceding years. Subjects with increasing concentrations of IL-6 or TNF-α between examinations were 5 times more likely to have progressed in joint space narrowing between the same examinations, as compared to those with stable or decreasing concentrations (OR 5.17; 1.54 to 17.32 and 5.01; 1.32 to 18.92).
Conclusions: In subjects with previous meniscectomy, higher or over time increasing synovial fluid levels of IL-6 and TNF-α seems to be associated with increased risk for progression of radiographic OA.
Circadian clocks and metabolism are inextricably intertwined, where central and hepatic circadian clocks coordinate metabolic events in response to light-dark and sleep-wake cycles. We reveal an additional key element involved in maintaining host circadian rhythms, the gut microbiome. Despite persistence of light-dark signals, germ-free mice fed low or high-fat diets exhibit markedly impaired central and hepatic circadian clock gene expression and do not gain weight compared to conventionally raised counterparts. Examination of gut microbiota in conventionally raised mice showed differential diurnal variation in microbial structure and function dependent upon dietary composition. Additionally, specific microbial metabolites induced under low- or high-fat feeding, particularly short-chain fatty acids, but not hydrogen sulfide, directly modulate circadian clock gene expression within hepatocytes. These results underscore the ability of microbially derived metabolites to regulate or modify central and hepatic circadian rhythm and host metabolic function, the latter following intake of a Westernized diet.
Copyright © 2015 Elsevier Inc. All rights reserved.
Unlabelled:
Osteoarthritis (OA) may result from intrinsic inflammation related to metabolic disturbance. Obesity-associated inflammation is triggered by lipopolysaccharide (LPS) derived from the gut microbiota. However, the relationship between gut microbiota, LPS, inflammation, and OA remain unclear.
Objective:
To evaluate the associations between gut microbiota, systemic LPS levels, serum and local inflammatory profiles, and joint damage in a high fat/high sucrose diet induced obese rat model.
Methods:
32 rats were randomized to a high fat/high sucrose diet (diet-induced obese (DIO), 40% fat, 45% sucrose, n = 21) or chow diet group (12% fat, 3.7% sucrose n = 11) for 28 weeks. After a 12-week obesity induction period, DIO animals were stratified into Obesity Prone (DIO-P, top 33% by change in body mass, n = 7), and Obesity Resistant groups (DIO-R, bottom 33%, n = 7). At sacrifice, joints were scored using a Modified Mankin Criteria. Blood and synovial fluid analytes, serum LPS, and fecal gut microbiota were analyzed.
Results:
DIO animals had greater Modified Mankin scores than chow animals (P = 0.002). There was a significant relationship (r = 0.604, p = 0.001) between body fat, but not body mass, and Modified Mankin score. Eighteen synovial fluid and four serum analytes were increased in DIO animals. DIO serum LPS levels were increased compared to chow (P = 0.031). Together, Lactobacillus species (spp.) and Methanobrevibacter spp. abundance had a strong predictive relationship with Modified Mankin Score (r(2) = 0.5, P < 0.001).
Conclusions:
Increased OA in DIO animals is associated with greater body fat, not body mass. The link between gut microbiota and adiposity-derived inflammation and metabolic OA warrants further investigation.
Tremendous progress has been made in characterizing the bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. A series of provocative preclinical studies have suggested a prominent role for the gut microbiota in these gut-brain interactions. Based on studies using rodents raised in a germ-free environment, the gut microbiota appears to influence the development of emotional behavior, stress- and pain-modulation systems, and brain neurotransmitter systems. Additionally, microbiota perturbations by probiotics and antibiotics exert modulatory effects on some of these measures in adult animals. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomic nervous system. Limited information is available on how these findings may translate to healthy humans or to disease states involving the brain or the gut/brain axis. Future research needs to focus on confirming that the rodent findings are translatable to human physiology and to diseases such as irritable bowel syndrome, autism, anxiety, depression, and Parkinson's disease.