Preclinical Models Of Osteoarthritis Research Articles

Factors affecting the reliability of behavioral assessments for rodent osteoarthritis models.

The translational value of osteoarthritis (OA) models is often debated because numerous studies have shown that animal models frequently fail to predict the efficacy of therapies in humans. In part, this failing may be due to the paucity of preclinical studies that include behavioral assessments in their metrics. Behavioral assessments of animal OA models can provide valuable data on the pain and disability associated with disease-sequelae of significant clinical relevance. Clinical definitions of efficacy for OA therapeutics often center on their palliative effects. Thus, the widespread inclusion of behaviors indicative of pain and disability in preclinical animal studies may contribute to greater success identifying clinically relevant interventions. Unfortunately, studies that include behavioral assays still frequently encounter pitfalls in assay selection, protocol consistency, and data/methods transparency. Targeted selection of behavioral assays, with consideration of the array of clinical OA phenotypes and the limitations of individual behavioral assays, is necessary to identify clinically relevant outcomes in OA animal models appropriately. Furthermore, to facilitate accurate comparisons across research groups and studies, it is necessary to improve the transparency of methods. Finally, establishing agreed-upon and clear definitions of behavioral data will reduce the convolution of data both within and between studies. Improvement in these areas is critical to the continued benefit of preclinical animal studies as translationally relevant data in OA research. As such, this review highlights the current state of behavioral analyses in preclinical OA models.

Hyperphysiological compression of articular cartilage induces an osteoarthritic phenotype in a cartilage-on-a-chip model.

Owing to population aging, the social impact of osteoarthritis (OA)-the most common musculoskeletal disease-is expected to increase dramatically. Yet, therapy is still limited to palliative treatments or surgical intervention, and disease-modifying OA (DMOA) drugs are scarce, mainly because of the absence of relevant preclinical OA models. Therefore, in vitro models that can reliably predict the efficacy of DMOA drugs are needed. Here, we show, using a newly developed microphysiological cartilage-on-a-chip model that enables the application of strain-controlled compression to three-dimensional articular cartilage microtissue, that a 30% confined compression recapitulates the mechanical factors involved in OA pathogenesis and is sufficient to induce OA traits. Such hyperphysiological compression triggers a shift in cartilage homeostasis towards catabolism and inflammation, hypertrophy, and the acquisition of a gene expression profile akin to those seen in clinical osteoarthritic tissue. The cartilage on-a-chip model may enable the screening of DMOA candidates.

Localized Osteoarthritis Disease-Modifying Changes due to Intra-articular Injection of Micronized Dehydrated Human Amnion/Chorion Membrane

Osteoarthritis (OA) is the leading cause of joint disability, and there are no FDA-approved disease-modifying drugs. The intra-articular delivery of micronized dehydrated human amnion/chorion membrane (AmnioFix, MiMedx, GA) has been shown to have a chondro-protective effect on articular cartilage in the medial meniscus transection (MMT) pre-clinical model of OA and has entered human clinical trials. AmnioFix is a well-characterized extracellular matrix (ECM)-derived therapeutic that contains hundreds of bioactive molecules, but little is known about its therapeutic mechanism in OA. The objective of this study was to elucidate, via local gene expression analysis, the molecular mechanisms of action of AmnioFix during OA development and progression. Lewis rats underwent MMT surgery, and AmnioFix or saline was injected intra-articularly 24 h post-surgery. At 5, 7, and 21 days post-surgery, articular cartilage, synovial membrane, and osteophyte tissues from multiple regions were collected and analyzed by microarray RT-PCR. Results demonstrated regional variation in the effects of amnion treatment on gene expression. Although gene expression was unaltered in articular cartilage and osteophyte tissue, pro- and anti-inflammatory markers were more highly expressed in the medial synovial membrane for the AmnioFix treatment group compared to the saline and naive control groups. These data suggest that the previously observed chondro-protective effects of AmnioFix treatment may be mediated via alteration of the synovial membrane microenvironment. This work is the first to provide insight into the mechanisms of action of AmnioFix within the articular joint space. AmnioFix (MiMedx, Marietta, GA), obtained from placenta, is a promising candidate for treatment of osteoarthritis (OA). AmnioFix has previously demonstrated protection of the cartilage on joint surfaces in an animal model of OA. However, this is the first study to elucidate the mechanisms of action of AmnioFix on multiple tissues within the joint space. Our results demonstrated that AmnioFix acts primarily through the synovial membrane, where it induces the expression of immunomodulatory markers. We suggest that the immunomodulatory properties of AmnioFix influence the microenvironment of the synovial membrane, thereby affecting joint homeostasis and inducing a chondro-protective effect on the articular cartilage. Future work should investigate the phenotype/s of cells recruited to the synovium following AmnioFix treatment, as well as the interaction of AmnioFix with synovial tissue-resident cells. Furthermore, the effects of AmnioFix on other joint disorders such as rheumatoid arthritis, a disease involving inflammation of the synovium, warrants further investigation.

Therapeutic efficacy of intra-articular delivery of encapsulated human mesenchymal stem cells on early stage osteoarthritis.

Mesenchymal stem cells (MSCs) represent a great therapeutic promise in pre-clinical models of osteoarthritis (OA), but many questions remain as to their therapeutic mechanism of action: engraftment versus paracrine action. Encapsulation of human MSCs (hMSCs) in sodium alginate microspheres allowed for the paracrine signaling properties of these cells to be isolated and studied independently of direct cellular engraftment. The objective of the present study was to quantitatively assess the efficacy of encapsulated hMSCs as a disease-modifying therapeutic for OA, using a medial meniscal tear (MMT) rat model. It was hypothesized that encapsulated hMSCs would have a therapeutic effect, through paracrine-mediated action, on early OA development.Lewis rats underwent MMT surgery to induce OA. 1 d post-surgery, rats received intra-articular injections of encapsulated hMSCs or controls (i.e., saline, empty capsules, non-encapsulated hMSCs). Microstructural changes in the knee joint were quantified using equilibrium partitioning of a ionic contrast agent based micro-computed tomography (EPIC-μCT) at 3 weeks post-surgery, an established time point for early OA.Encapsulated hMSCs significantly attenuated MMT-induced increases in articular cartilage swelling and surface roughness and augmented cartilaginous and mineralized osteophyte volumes.Cellular encapsulation allowed to isolate the hMSC paracrine signaling effects and demonstrated that hMSCs could exert a chondroprotective therapeutic role on early stage OA through paracrine signaling alone. In addition to this chondroprotective role, encapsulated hMSCs augmented the compensatory increases in osteophyte formation. The latter should be taken into strong consideration as many clinical trials using MSCs for OA are currently ongoing.

The limited knee range of motion causes progression of cartilage degeneration in the osteoarthritic knee joint: an experimental study using a preclinical model of osteoarthritis

The limited knee range of motion causes progression of cartilage degeneration in the osteoarthritic knee joint: an experimental study using a preclinical model of osteoarthritis

SM04690, a WNT pathway inhibitor: anti-inflammatory and cartilage protective effects in preclinical osteoarthritis models

Purpose: Osteoarthritis (OA) is characterized by pain, swelling, and reduced function in the knee joint. Upregulated Wnt signaling drives OA through synovial inflammation, increased subchondral bone, and thinning cartilage. SM04690, a small molecule Wnt pathway inhibitor that demonstrated chondrogenesis and anti-inflammatory properties preclinically (Deshmukh et al., OAC 2017; Deshmukh et al. Arth Rheum 2016), was further evaluated to determine its potential to reduce inflammation, protect cartilage, improve joint health and modify pain in OA. Methods: Cytokine secretion (IL-6 and TNF-α) from IL-1β stimulated- and SM04690 treated-synovial fibroblasts was measured by ELISA. A single intra-articular injection of SM04690 or vehicle was evaluated in an in vivo rat knee monosodium iodoacetate (MIA) OA model. Joint inflammation was evaluated by H&E staining, inflammatory cytokines (IL-1α, IL-1β, IL-6, TNF-α and IFN-γ) by qPCR, and cartilage protection by qPCR for matrix metalloproteinases (MMPs). Histological evaluation of cartilage health was performed using OARSI score and thickness by Safranin-O staining. Pain was measured as paw withdrawal threshold using Von Frey apparatus and weight distribution using incapacitance meter and analyzed using generalized estimating equation regression accounting for repeated measurements. Results: SM04690 dose-dependently inhibited IL-1β-induced cytokine secretion in synovial fibroblasts (EC50 ∼30nM; Fig.1). In the rat MIA OA model, compared to vehicle, SM04690 injection reduced visible knee swelling, inflammatory cells, proinflammatory cytokine and MMP production (P < 0.05). SM04690 increased (P < 0.01) paw withdrawal threshold and improved (P < 0.05) weight distribution to the affected limb in treated rats, at all post-treatment timepoints, compared to vehicle. SM04690 increased Safranin-O stained cartilage thickness and decreased OARSI score (P < 0.05) compared to vehicle (Fig.2). Conclusions: In a rat MIA OA model, SM04690 injection reduced inflammation, protease production, and pain, with improved cartilage and joint health, compared to vehicle. Previously demonstrated regenerative effects in nonclinical studies1, along with anti-inflammatory properties, show SM04690 may potentially improve symptoms and provide disease modification in OA. Clinical studies are ongoing.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Controlled release of celecoxib inhibits inflammation, bone cysts and osteophyte formation in a preclinical model of osteoarthritis

Major hallmarks of osteoarthritis (OA) are cartilage degeneration, inflammation and osteophyte formation. COX-2 inhibitors counteract inflammation-related pain, but their prolonged oral use entails the risk for side effects. Local and prolonged administration in biocompatible and degradable drug delivery biomaterials could offer an efficient and safe treatment for the long-term management of OA symptoms. Therefore, we evaluated the disease-modifying effects and the optimal dose of polyesteramide microspheres delivering the COX-2 inhibitor celecoxib in a rat OA model. Four weeks after OA induction by anterior cruciate ligament transection and partial medial meniscectomy, 8-week-old female rats (n = 6/group) were injected intra-articular with celecoxib-loaded microspheres at three dosages (0.03, 0.23 or 0.39 mg). Unloaded microspheres served as control. During the 16-week follow-up, static weight bearing and plasma celecoxib concentrations were monitored. Post-mortem, micro-computed tomography and knee joint histology determined progression of synovitis, osteophyte formation, subchondral bone changes, and cartilage integrity. Systemic celecoxib levels were below the detection limit 6 days upon delivery. Systemic and local adverse effects were absent. Local delivery of celecoxib reduced the formation of osteophytes, subchondral sclerosis, bone cysts and calcified loose bodies, and reduced synovial inflammation, while cartilage histology was unaffected. Even though the effects on pain could not be evualated directly in the current model, our results suggest the application of celecoxib-loaded microspheres holds promise as novel, safe and effective treatment for inflammation and pain in OA.

Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis

Mesenchymal stem or stromal cells (MSCs) exert chondroprotective effects in preclinical models of osteoarthritis (OA). Most of their therapeutic effects are mediated via soluble mediators, which can be conveyed within extracellular vesicles (EVs). The objective of the study was to compare the respective role of exosomes (Exos) or microvesicles/microparticles (MPs) in OA. MPs and Exos were isolated from bone marrow murine BM-MSCs through differential centrifugation. Effect of MPs or Exos was evaluated on OA-like murine chondrocytes and chondroprotection was quantified by RT-qPCR. In OA-like chondrocytes, BM-MSC-derived MPs and Exos could reinduce the expression of chondrocyte markers (type II collagen, aggrecan) while inhibiting catabolic (MMP-13, ADAMTS5) and inflammatory (iNOS) markers. Exos and MPs were also shown to protect chondrocytes from apoptosis and to inhibit macrophage activation. In vivo, Exos or MPs were injected in the collagenase-induced OA (CIOA) model and histomorphometric analyses of joints were performed by µCT and confocal laser microscopy. BM-MSCs, MPs and Exos equally protected mice from joint damage. In conclusion, MPs and Exos exerted similar chondroprotective and anti-inflammatory function in vitro and protected mice from developing OA in vivo, suggesting that either Exos or MPs reproduced the main therapeutic effect of BM-MSCs.

Contrast enhanced μCT imaging of early articular changes in a pre-clinical model of osteoarthritis.

The objective of this study was to characterize early osteoarthritis (OA) development in cartilage and bone tissues in the rat medial meniscus transection (MMT) model using non-destructive equilibrium partitioning of an ionic contrast agent micro-computed tomography (EPIC-μCT) imaging. Cartilage fibrillation, one of the first physiological developments in OA, was quantified in the rat tibial plateau as three-dimensional (3D) cartilage surface roughness using a custom surface-rendering algorithm. Male Lewis rats underwent MMT or sham-operation in the left leg. At 1- and 3-weeks post-surgery, the animals (n=7-8 per group) were euthanized and the left legs were scanned using EPIC-μCT imaging to quantify cartilage and bone parameters. In addition, a custom algorithm was developed to measure the roughness of 3D surfaces. This algorithm was validated and used to quantify cartilage surface roughness changes as a function of time post-surgery. MMT surgery resulted in significantly greater cartilage damage and subchondral bone sclerosis with the damage increasing in both severity and area from 1- to 3-weeks post-surgery. Analysis of rendered 3D surfaces could accurately distinguish early changes in joints developing OA, detecting significant increases of 45% and 124% in surface roughness at 1- and 3-weeks post-surgery respectively. Disease progression in the MMT model progresses sequentially through changes in the cartilage articular surface, extracellular matrix composition, and then osteophyte mineralization and subchondral bone sclerosis. Cartilage surface roughness is a quantitative, early indicator of degenerative joint disease in small animal OA models and can potentially be used to evaluate therapeutic strategies.

Resveratrol, Potential Therapeutic Interest in Joint Disorders: A Critical Narrative Review.

Trans-resveratrol (t-Res) is a natural compound of a family of hydroxystilbenes found in a variety of spermatophyte plants. Because of its effects on lipids and arachidonic acid metabolisms, and its antioxidant activity, t-Res is considered as the major cardioprotective component of red wine, leading to the “French Paradox” health concept. In the past decade, research on the effects of resveratrol on human health has developed considerably in diverse fields such as cancer, neurodegenerative and cardiovascular diseases, and metabolic disorders. In the field of rheumatic disorders, in vitro evidence suggest anti-inflammatory, anti-catabolic, anti-apoptotic and anti-oxidative properties of t-Res in various articular cell types, including chondrocytes and synoviocytes, along with immunomodulation properties on T and B lymphocytes. In preclinical models of osteoarthritis and rheumatoid arthritis, resveratrol has shown joint protective effects, mainly mediated by decreased production of pro-inflammatory and pro-degradative soluble factors, and modulation of cellular and humoral responses. Herein, we comprehensively reviewed evidence supporting a potential therapeutic interest of t-Res in treating symptoms related to rheumatic disorders.

Emerging Targets for the Management of Osteoarthritis Pain.

Worldwide, osteoarthritis (OA) is one of the leading causes of chronic pain, for which adequate relief is not available. Ongoing peripheral input from the affected joint is a major factor in OA-associated pain. Therefore, this review focuses predominantly on peripheral targets emerging in the preclinical and clinical arena. Nerve growth factor is the most advanced of these targets, and its blockade has shown tremendous promise in clinical trials in knee OA. A number of different types of ion channels, including voltage-gated sodium channels and calcium channels, transient receptor potential channels, and acid-sensing ion channels, are important for neuronal excitability and play a role in pain genesis. Few channel blockers have been tested in preclinical models of OA, with varying results. Finally, we discuss some examples of G-protein coupled receptors, which may offer attractive therapeutic strategies for OA pain, including receptors for bradykinin, calcitonin gene-related peptide, and chemokines. Since many of the pathways described above can be selectively and potently targeted, they offer an exciting opportunity for pain management in OA, either systemically or locally.

MSC signature associated with therapeutical effect in osteoarticular diseases

Adipose derived mesenchymal stromal cells (ASC) are adult stem cells exhibiting functional properties that have open the way for cell-based clinical therapies. Primarily, their capacity of multilineage differentiation has been explored in a number of strategies for skeletal tissue regeneration. More recently, MSCs have been reported to exhibit immunosuppressive as well as healing capacities, to improve angiogenesis and prevent apoptosis or fibrosis through the secretion of paracrine mediators including HGF, IL1RA, IL-6, PDL-1, TSG6, TGF-β1 and PGE2. In normal homeostasis, IL1Ra counterbalances the effect of IL1α and IL1β as a competitive receptor antagonist. MSC immunosuppressive effect is highly variable according to cell population heterogeneity. We compared gene expression of huMSC with high potential to inhibit T cells response with low efficient MSC through gene array. We identified a signature associated with high immunoregulatory function. High expression of ITPR1, NR4A3, ABCA1, LIPG ADAMTS4 as well as expression of CD109, ITGA10, IL6R was associated with increased T cell suppressive effect in vitro. We performed preclinical models of osteoarthritis, and showed that a local injection of ASC showed a reduction of synovitis, reduction of osteophytes, joint stabilization, reducing the score of cartilage lesions. We then investigated the role of iNOS, IL6 and IL1RA respectively using the inflammatory collagen-induced arthritis model. In contrast to wt MSCs, which reduced both the incidence and clinical signs of arthritis, IL1RA–/– MSCs were not able to prevent arthritis progression and even worsened the arthritic symptoms. μCT analysis showed a protection against bone erosion by wt MSCs but not in IL1RA–/–MSCs-treated mice. We found a decrease of the number of CD4 + IFN-γ+ Th1 and CD4 + IL-17+ Th17 lymphocytes in the spleens of wt MSCs-treated mice as compared to IL1RA–/– MSCs-treated mice. This work was completed by toxicology data showing the excellent tolerance of the local injection of ADSC and biodistribution showing the persistence of cells after 6 months in murine models. We conducted a open-label phase 1 trial including 18 patients with severe osteoarthritis of the knee in failure of conventional therapies (62.5% were KL IV) at two sites, Montpellier and Wurzburg. Mean age was 61 years, with a 10 years history of knee OA. The patient received a single injection of autologous ASC 15 days after lipoaspiration (2.106, 107 or 5.107) through intra-articular injection. The primary outcome measure of effectiveness was patient-reported WOMAC pain subscores by VAS in the affected knee at week 12. Secondary outcome measures included Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT OARSI) responses. We observed a decrease of the VAS Pain (73 ± 11 mm day 0 to 32 ± 23 month 3), and of WOMAC (50 ± 18 to 25 ± 7 month 3). This study confirms the feasibility and safety of local injection of autologous cells from adipose tissue and suggested that the most effective dose was 107 autologous cells. Moreover, a molecular signature associated with increase immunosuppressive potential is described.

Spontaneous burrowing behavior as an outcome measure of the global impact of chronic pain in preclinical models of arthritis

Abstract Aims Arthritis is the leading cause of chronic pain in European adults (painineurope.com). Arthritis-induced chronic pain is a major clinical problem that is frequently inadequately treated by current analgesics and results in significant reduction in the patient’s quality of life. Outcome measures used in pain research to assess injury-induced pain-like behaviours in preclinical models are often dependent on the assessment of withdrawal reflexes, typically evoked by mechanical or thermal stimuli.Advances inpre-dictive validity may be improved by assessing the global impact of pain and the reinstatement of innate behaviours suppressed by injury. Burrowing, an indicator of the global “wellbeing” of the animal can be objectively measured. We aimed to assess the impact of several preclinical modelsof arthritis onburrowing behaviour in mice. Methods The collagen antibody-induced arthritis (CAIA) pre-clinical model of rheumatoid arthritis, the complete Freund’s adjuvant (CFA), monosodium iodoacetate (MIA) and partial medial menisectomy (MMT) preclinical models of osteoarthritis were assessed in female and/or male C57/Black6J adult mice, comparing to control (salineorsham-operated) and naïve animals. Mechanical hypersensitivity using von Frey filaments and spontaneous burrowing behaviour were assessed over60days (CAIA), 14days (CFA), 28 days (MIA) and up to 200 days (MMT). Results We show the development of mechanical hypersen-sitivity in all preclinical models of arthritis, whereas spontaneous burrowing behaviour was altered differently between the preclin-ical models. A deficit in burrowing behaviour was observed in the preclinical models of osteoarthritis and a gain in burrowing behaviour noted in the preclinical model of rheumatoid arthritis, with no effect seen in the CFA model. Conclusions Burrowing behaviour appears more sensitive to detecting variation in preclinical models of arthritis when compared to mechanical hypersensitivity. Burrowing behaviour can detect both gain and deficits in the behaviour, which differs between preclinical models of rheumatoid and osteoarthritis.

TRPV1 antagonists in the treatment of osteoarthritis pain

Pain is the dominant symptom of osteoarthritis (OA) and available analgesic treatments offer inadequate pain relief. The capsaicin receptor, TRPV1 is considered to be a promising analgesic target. TRPV1 is expressed in multiple cell types of the joint. A variant of the TRPV1 gene is associated with the risk of developing symptomatic OA and synovial TRPV1 expression is increased in OA patients undergoing total joint replacement. Potent and selective small molecule TRPV1 antagonists have analgesic effects in preclinical models of OA highlighting the potential utility of TRPV1 antagonists in OA pain management. However, use of these compounds is associated with serious on-target-mediated side effects and analgesic efficacy in OA patients in clinical trials remains to be proven. This review article will discuss recent findings in this area and explore the potential utility of TRPV1 antagonists in the treatment of OA pain.

Endocannabinoids and acute pain after total knee arthroplasty.

Osteoarthritis (OA) of the knee is a progressive disease that is associated with inflammation of the joints and lower extremity pain. Total knee arthroplasty (TKA) is a surgical procedure that aims to reduce pain and restore motor function in patients suffering from OA. The immediate postoperative period can be intensely painful leading to extended recovery times including persistent pain. The endocannabinoid system regulates nociception, and the activation of cannabinoid receptors produces antinociceptive effects in preclinical models of OA. To date, the influence of the endocannabinoid tone on pain and disability in OA patients and on acute postoperative pain in humans has not been explored. In this study, we provide the first comprehensive profile of endocannabinoids in serum, cerebrospinal fluid, and synovial fluid of patients with painful end-stage OA undergoing TKA and examine correlations between endocannabinoid levels, interleukin 6, functional disability, acute postoperative pain, and postoperative opioid use. Our results reveal that central (cerebrospinal fluid) and peripheral (synovial fluid) levels of the endocannabinoid 2-arachidonoyl glycerol were significantly elevated in patients who developed higher postoperative pain after TKA. In addition, synovial fluid 2-arachidonoyl glycerol levels were positively correlated with postoperative opioid use. Similarly, synovial fluid levels of the anti-inflammatory lipid palmitoylethanolamide correlated with functional disability in OA. Taken together, our results are the first to reveal associations between central and peripheral endocannabinoid levels and postoperative pain. This suggests that endocannabinoid metabolism may serve as a target for the development of novel analgesics both for systemic or local delivery into the joint.

Comparing the disease modifying effects of alendronate to risedronate in the rat anterior cruciate ligament transection model of osteoarthritis

Comparing the disease modifying effects of alendronate to risedronate in the rat anterior cruciate ligament transection model of osteoarthritis

Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: Role of secretome and exosomes

Over the last decades, mesenchymal stem cells (MSCs) have been extensively studied with regard to their potential applications in regenerative medicine. In rheumatic diseases, MSC-based therapy is the subject of great expectations for patients who are refractory to proposed treatments such as rheumatoid arthritis (RA), or display degenerative injuries without possible curative treatment, such as osteoarthritis (OA). The therapeutic potential of MSCs has been demonstrated in several pre-clinical models of OA or RA and both the safety and efficacy of MSC-based therapy is being evaluated in humans. The predominant mechanism by which MSCs participate to tissue repair is through a paracrine activity. Via the production of a multitude of trophic factors with various properties, MSCs can reduce tissue injury, protect tissue from further degradation and/or enhance tissue repair. However, a thorough in vivo examination of MSC-derived secretome and strategies to modulate it are still lacking. The present review discusses the current understanding of the MSC secretome as a therapeutic for treatment of inflammatory or degenerative pathologies focusing on rheumatic diseases. We provide insights on and perspectives for future development of the MSC secretome with respect to the release of extracellular vesicles that would have certain advantages over injection of living MSCs or administration of a single therapeutic factor or a combination of factors.

Hormonal modulation of connective tissue homeostasis and sex differences in risk for osteoarthritis of the knee

Young female athletes experience a higher incidence of ligament injuries than their male counterparts, females experience a higher incidence of joint hypermobility syndrome (a risk factor for osteoarthritis development), and post-menopausal females experience a higher prevalence of osteoarthritis than age-matched males. These observations indicate that fluctuating sex hormone levels in young females and loss of ovarian sex hormone production due to menopause likely contribute to observed sex differences in knee joint function and risk for loss of function. In studies of osteoarthritis, however, there is a general lack of appreciation for the heterogeneity of hormonal control in both women and men. Progress in this field is limited by the relatively few preclinical osteoarthritis models, and that most of the work with established models uses only male animals. To elucidate sex differences in osteoarthritis, it is important to examine sex hormone mechanisms in cells from knee tissues and the sexual dimorphism in the role of inflammation at the cell, tissue, and organ levels. There is a need to determine if the risk for loss of knee function and integrity in females is restricted to only the knee or if sex-specific changes in other tissues play a role. This paper discusses these gaps in knowledge and suggests remedies.

Pharmacological modulation of brain activity in a preclinical model of osteoarthritis

The earliest stages of osteoarthritis are characterized by peripheral pathology; however, during disease progression chronic pain emerges-a major symptom of osteoarthritis linked to neuroplasticity. Recent clinical imaging studies involving chronic pain patients, including osteoarthritis patients, have demonstrated that functional properties of the brain are altered, and these functional changes are correlated with subjective behavioral pain measures. Currently, preclinical osteoarthritis studies have not assessed if functional properties of supraspinal pain circuitry are altered, and if these functional properties can be modulated by pharmacological therapy either by direct or indirect action on brain systems. In the current study, functional connectivity was first assessed in order to characterize the functional neuroplasticity occurring in the rodent medial meniscus tear (MMT) model of osteoarthritis-a surgical model of osteoarthritis possessing peripheral joint trauma and a hypersensitive pain state. In addition to knee joint trauma at week 3 post-MMT surgery, we observed that supraspinal networks have increased functional connectivity relative to sham animals. Importantly, we observed that early and sustained treatment with a novel, peripherally acting broad-spectrum matrix metalloproteinase (MMP) inhibitor (MMPi) significantly attenuates knee joint trauma (cartilage degradation) as well as supraspinal functional connectivity increases in MMT animals. At week 5 post-MMT surgery, the acute pharmacodynamic effects of celecoxib (selective cyclooxygenase-2 inhibitor) on brain function were evaluated using pharmacological magnetic resonance imaging (phMRI) and functional connectivity analysis. Celecoxib was chosen as a comparator, given its clinical efficacy for alleviating pain in osteoarthritis patients and its peripheral and central pharmacological action. Relative to the vehicle condition, acute celecoxib treatment in MMT animals yielded decreased phMRI infusion responses and decreased functional connectivity, the latter observation being similar to what was detected following chronic MMPi treatment. These findings demonstrate that an assessment of brain function may provide an objective means by which to further evaluate the pathology of an osteoarthritis state as well as measure the pharmacodynamic effects of therapies with peripheral or peripheral and central pharmacological action.

Kinematic and dynamic gait compensations resulting from knee instability in a rat model of osteoarthritis

IntroductionOsteoarthritis (OA) results in pain and disability; however, preclinical OA models often focus on joint-level changes. Gait analysis is one method used to evaluate both preclinical OA models and OA patients. The objective of this study is to describe spatiotemporal and ground reaction force changes in a rat medial meniscus transection (MMT) model of knee OA and to compare these gait measures with assays of weight bearing and tactile allodynia.MethodsSixteen rats were used in the study. The medial collateral ligament (MCL) was transected in twelve Lewis rats (male, 200 to 250 g); in six rats, the medial meniscus was transected, and the remaining six rats served as sham controls. The remaining four rats served as naïve controls. Gait, weight-bearing as measured by an incapacitance meter, and tactile allodynia were assessed on postoperative days 9 to 24. On day 28, knee joints were collected for histology. Cytokine concentrations in the serum were assessed with a 10-plex cytokine panel.ResultsWeight bearing was not affected by sham or MMT surgery; however, the MMT group had decreased mechanical paw-withdrawal thresholds in the operated limb relative to the contralateral limb (P = 0.017). The gait of the MMT group became increasingly asymmetric from postoperative days 9 to 24 (P = 0.020); moreover, MMT animals tended to spend more time on their contralateral limb than their operated limb while walking (P < 0.1). Ground reaction forces confirmed temporal shifts in symmetry and stance time, as the MMT group had lower vertical and propulsive ground reaction forces in their operated limb relative to the contralateral limb, naïve, and sham controls (P < 0.05). Levels of interleukin 6 in the MMT group tended to be higher than naïve controls (P = 0.072). Histology confirmed increased cartilage damage in the MMT group, consistent with OA initiation. Post hoc analysis revealed that gait symmetry, stance time imbalance, peak propulsive force, and serum interleukin 6 concentrations had significant correlations to the severity of cartilage lesion formation.ConclusionThese data indicate significant gait compensations were present in the MMT group relative to medial collateral ligament (MCL) injury (sham) alone and naïve controls. Moreover, these data suggest that gait compensations are likely driven by meniscal instability and/or cartilage damage, and not by MCL injury alone.