Articular Destruction Research Articles

Cartilage Repair by Mesenchymal Stem Cell-Derived Exosomes: Preclinical and Clinical Trial Update and Perspectives.

Osteoarthritis (OA) and other degenerative joint diseases are characterized by articular cartilage destruction, synovial inflammation, sclerosis of subchondral bone, and loss of extracellular matrix (ECM). Worldwide, these diseases are major causes of disability. Cell therapies have been considered to be the best therapeutic strategies for long-term treatment of articular cartilage diseases. It has been suggested that the mechanism of stem cell-based therapy is related to paracrine secretion of extracellular vesicles (EVs), which are recognized as the main secretion factors of stem cells. EVs, and in particular the subclass exosomes (Exos), are novel therapeutic approaches for treatment of cartilage lesions and OA. The results of recent studies have shown that EVs isolated from mesenchymal stem cells (MSCs) could inhibit OA progression. EVs isolated from various stem cell sources, such as MSCs, may contribute to tissue regeneration of the limbs, skin, heart, and other tissues. Here, we summarize recent findings of preclinical and clinical studies on different MSC-derived EVs and their effectiveness as a treatment for damaged cartilage. The Exos isolation techniques in OA treatment are also highlighted.

Activation of TRPV4 by mechanical, osmotic or pharmaceutical stimulation is anti-inflammatory blocking IL-1β mediated articular cartilage matrix destruction

SummaryObjectiveCartilage health is maintained in response to a range of mechanical stimuli including compressive, shear and tensile strains and associated alterations in osmolality. The osmotic-sensitive ion channel Transient Receptor Potential Vanilloid 4 (TRPV4) is required for mechanotransduction. Mechanical stimuli inhibit interleukin-1β (IL-1β) mediated inflammatory signalling, however the mechanism is unclear. This study aims to clarify the role of TRPV4 in this response.DesignTRPV4 activity was modulated glycogen synthase kinase (GSK205 antagonist or GSK1016790 A (GSK101) agonist) in articular chondrocytes and cartilage explants in the presence or absence of IL-1β, mechanical (10% cyclic tensile strain (CTS), 0.33 Hz, 24hrs) or osmotic loading (200mOsm, 24hrs). Nitric oxide (NO), prostaglandin E2 (PGE2) and sulphated glycosaminoglycan (sGAG) release and cartilage biomechanics were analysed. Alterations in post-translational tubulin modifications and primary cilia length regulation were examined.ResultsIn isolated chondrocytes, mechanical loading inhibited IL-1β mediated NO and PGE2 release. This response was inhibited by GSK205. Similarly, osmotic loading was anti-inflammatory in cells and explants, this response was abrogated by TRPV4 inhibition. In explants, GSK101 inhibited IL-1β mediated NO release and prevented cartilage degradation and loss of mechanical properties. Upon activation, TRPV4 cilia localisation was increased resulting in histone deacetylase 6 (HDAC6)-dependent modulation of soluble tubulin and altered cilia length regulation.ConclusionMechanical, osmotic or pharmaceutical activation of TRPV4 regulates HDAC6-dependent modulation of ciliary tubulin and is anti-inflammatory. This study reveals for the first time, the potential of TRPV4 manipulation as a novel therapeutic mechanism to supress pro-inflammatory signalling and cartilage degradation.

An interdigitated aptasensor to detect interleukin-6 for diagnosing rheumatoid arthritis in serum.

Rheumatoid arthritis (RA) is an autoimmune disorder causing chronic inflammation in the small joints of the articular bone and destruction of articular cartilage. RA causes stiffness, pain, joint destruction, substantial comorbidity, and functional disability. Early-stage diagnosis of RA can help in the treatment of the disease and expand the patient life span. Interleukins are a group of inflammatory cytokines; in particular, an abundance of interleukin-6 (IL-6) was found in the synovial fluid and serum. In RA patients, the levels of IL-6 have been found to be correlated with the disease, and this work focused on detecting IL-6 by its aptamer with the help of a biotin-streptavidin strategy on an interdigitated electrode. A sensitivity of 1fM (0.021pg/mL) and a limit of detection of 10fM (0.21pg/mL) were found by a linear regression [y=0.6413x-0.6249; R²=0.952] of the linear range from 1fM to 100pM. This method enhanced the immobilization of higher aptamer molecules for recognizing RA in serum-containing samples and is applicable to other diseases.

Costal cartilage graft for an unstable post-traumatic trapeziometacarpal intra-articular malunion in a pediatric patient: A case report

Trapeziometacarpal dislocation is a rare traumatic lesion, especially in the pediatric population. Various treatments have been described for acute cases. We report the case of a 15-year-old boy who was admitted in the emergency department with chronic post-traumatic trapeziometacarpal dislocation due to an untreated first metacarpal base fracture (Bennett), with complete articular destruction. The patient was treated by open reduction, interposition of a costal cartilage graft, and intermetacarpal K-wire fixation. Follow-up at 2 years after the surgery showed excellent clinical and radiological results. This surgical technique had not been described previously in the pediatric population.

Ginkgolide B attenuates collagen-induced rheumatoid arthritis and regulates fibroblast-like synoviocytes-mediated apoptosis and inflammation.

BackgroundRheumatoid arthritis (RA) is a systemic disease characterized by chronic synovial infiltration and proliferation, cartilage destruction, and joint injury. Ginkgolide B (GB) is an extract of the leaves of Ginkgo biloba, and pharmacological studies have shown that it has anti-inflammatory and anti-apoptotic activities. The purpose of this study was to investigate the anti-RA properties of GB.MethodsIn vivo, we established a collagen II-induced arthritis (CIA) mouse model. Mice were divided into five groups (n=10): sham, CIA, GB (10 µM), GB (20 µM), and GB (40 µM). We measured arthritis score, synovial histopathological change, and peripheral blood cytokine levels. In vitro, we used lipopolysaccharide (LPS)-induced-fibroblast-like synoviocytes (RA-FLSs) as the study subject. Cell viability, apoptosis, and inflammatory cytokines levels were detected by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, flow cytometry, and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), respectively. Finally, the protein expression of wingless-type family member 5A (Wnt5a), c-Jun N-terminal kinase (JNK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 were detected by Western blot.ResultsArthritis scores, synovial hyperplasia, and cartilage and bone destruction were significantly ameliorated by GB. Additionally, GB decreased the serum levels of interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α), matrix metalloproteinase (MMP)-3 and MMP-13, and increased IL-10. In vitro, we found that GB remarkably inhibited RA-FLSs viability at 24 or 48 h in a concentration-dependent manner. The apoptotic ratio was reduced by GB, and it increased the expression of cleaved-Caspase-3 and Bax while decreasing Bcl-2 expression in RA-FLSs. Furthermore, GB attenuated the progression of inflammation by mediating inflammatory cytokine release and MMPs gene expression. Meanwhile, GB inactivated the expression levels of Wnt5a, phosphorylated (p)-JNK, and p-P65 in the synovial tissues and RA-FLSs.ConclusionsThis study was the first to demonstrate that the anti-RA effect of GB is related to reducing articular cartilage and bone destruction, inducing RA-FLSs apoptosis, and regulating inflammatory cytokine release and the Wnt5a/JNK/NF-κB axis. All the findings highlight that GB might provide a novel treatment approach for RA.

Relationship Between Magnetic Resonance T2-Mapping and Matrix Metalloproteinase 1,3 in Knee Osteoarthritis

ObjectiveTo investigate the relationship between quantitative analysis of MRI (T2-mapping) and the expression of matrix metalloproteinase (MMP-1, MMP-3) in osteoarthritis of the knee joint and the role of MMP-1,3 in the pathogenesis of osteoarthritis.MethodsThirty cases of knee osteoarthritis (KOA) patients with total knee arthroplasty (TKA) (lesion group) and 30 healthy adult volunteers (control group) were scanned with 1.5 T routine MR and T2-mapping, and their T2 values were measured and statistically analyzed. The pathological examination of the knee cartilage that was replaced during the operation and the immunohistochemical assay were used to measure the expression of MMP-1,3. The correlation between the T2 value of magnetic resonance imaging and the expression of MMP-1,3 was analyzed.Results(1) According to the Recht grading standard for magnetic resonance, the T2 value of magnetic resonance increased significantly with the increase of cartilage degeneration. The differences in T2 values between each level and the normal group were statistically significant (P < 0.05). (2) The T2 value of magnetic resonance imaging increased with the severity of the cartilage degeneration pathological Mankin grading, and the difference was statistically significant (P < 0.05). (3) The expression of MMP-1,3 increased with cartilage degeneration. (4) The T2 value and the expression of MMP-1 in cartilage showed a linear trend. The result of Spearman correlation analysis showed that the expression of MMP-1,3 increased as the cartilage T2 value increased. There was a positive linear correlation between the two.ConclusionThe T2 value of magnetic resonance increased with the degeneration of KOA cartilage. The expression of MMP-1,3 increased with the severity of articular cartilage destruction. The T2 value of KOA magnetic resonance was positively correlated with the expression of MMP-1,3.

Long non-coding RNA XIST regulates chondrogenic differentiation of synovium-derived mesenchymal stem cells from temporomandibular joint via miR-27b-3p/ADAMTS-5 axis

ObjectiveTemporomandibular joint osteoarthritis (TMJOA) is a common degenerative disease in jaw joint, accompanied by articular cartilage destruction. Differentiation of stem cells to cartilage has important therapeutic implications in TMJ cartilage repair. Previous studies revealed that lncRNA XIST participated in various biological processes. However, the effect of XIST on chondrogenic differentiation of synovium-derived mesenchymal stem cells (SMSCs) remains unclear. Our study aimed to investigate the function of XIST in chondrogenic differentiation of human SMSCs from TMJ. MethodsAlcian blue staining was performed to determine proteoglycan in SMSCs. qPCR, western blotting and immunofluorescence assays were allowed to assess sex determining region Y-box 9 (SOX9), Collagen type II alpha 1 chain (COL2A1) and Aggrecan (ACAN) expression. The direct interaction between miR-27b-3p and XIST or ADAMTS-5 was confirmed by dual luciferase reporter assay or RNA immunoprecipitation (RIP) assay. ResultsXIST was remarkably down-regulated in chondrogenic differentiation of SMSCs. Functional analysis demonstrated that XIST silencing promoted chondrogenic differentiation of SMSCs. Dual luciferase reporter and RIP assays identified that XIST acted as a sponge for miR-27b-3p. Moreover, XIST regulated ADAMTS-5 expression by directly binding miR-27b-3p. More importantly, miR-27b-3p/ADAMTS-5 rescued the effects of XIST on chondrogenic differentiation of SMSCs. ConclusionThe results suggest that XIST modulates SMSCs chondrogenic differentiation via the miR-27b-3p/ADAMTS-5 axis, which provides new targets for TMJOA treatment.

Knee arthroplasty for acute fractures around the knee.

Results of open reduction and internal fixation for complex articular fractures around the knee are poor, particularly in elderly osteoporotic patients.Open reduction and internal fixation may lead to an extended hospital stay and non-weight-bearing period.This may lead to occurrence of complications related to decubitus such as thrombo-embolic events, pneumonia and disorientation.Primary arthroplasty can be a valuable option in a case-based and patient-specific approach. It may reduce the number of procedures and allow early full weight-bearing, avoiding the above-mentioned complications.There are four main indications: 1) Elderly (osteoporotic) patients with pre-existing (symptomatic) end-stage osteoarthritis.2) Elderly (osteoporotic) patients with severe articular and metaphyseal destruction.3) Pathological fractures of the distal femur and/or tibia.4) Young patients with complete destruction of the distal femur and/or tibia.The principles of knee (revision) arthroplasty should be applied; choice of implant and level of constraint should be considered depending on the type of fracture and involvement of stabilizing ligaments. The aim of treatment is to obtain a stable and functional joint.Long-term data remain scarce in the literature due to limited indications.Cite this article: EFORT Open Rev 2020;5:713-723. DOI: 10.1302/2058-5241.5.190059

Osteoclast-associated receptor blockade prevents articular cartilage destruction via chondrocyte apoptosis regulation

Osteoarthritis (OA), primarily characterized by articular cartilage destruction, is the most common form of age-related degenerative whole-joint disease. No disease-modifying treatments for OA are currently available. Although OA is primarily characterized by cartilage destruction, our understanding of the processes controlling OA progression is poor. Here, we report the association of OA with increased levels of osteoclast-associated receptor (OSCAR), an immunoglobulin-like collagen-recognition receptor. In mice, OSCAR deletion abrogates OA manifestations, such as articular cartilage destruction, subchondral bone sclerosis, and hyaline cartilage loss. These effects are a result of decreased chondrocyte apoptosis, which is caused by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in induced OA. Treatments with human OSCAR-Fc fusion protein attenuates OA pathogenesis caused by experimental OA. Thus, this work highlights the function of OSCAR as a catabolic regulator of OA pathogenesis, indicating that OSCAR blockade is a potential therapy for OA.

Neuropeptides and Articular Cartilage Pathology: Harmful or Helpful or Both?

BACKGROUND: Osteoarthritis, a major cause of chronic disabling pain among older adults has long been considered a non-inflammatory “wear and tear” disease associated with aging that largely implicates the loss of articular cartilage of one or more freely moving joints such the knee and hip as a result of biomechanical mechanisms. Recent findings however, imply that in addition to mechanical disruption of an affected joint, its disabling features, including pain, inflammatory mechanisms, and changes in the synovium surrounding the joint play a pivotal role in this regard. QUESTIONS: Do neuropeptides, small protein like molecules involved in neural transmission processes play a pivotal role in pathogenesis of osteoarthritis associated articular cartilage pathological changes, and can this information be applied clinically, to prevent or ameliorate the condition, and if so how? METHODS: PUBMED, SCOPUS, and WEB OF SCIENCE articles related to the topic were searched and examined and reported in narrative form. RESULTS: Neuropeptides are widespread neural modulators within the central and peripheral nervous system. Both excess as well as deficient neuropeptide production may prove harmful to articular cartilage, the tissue affected most clearly in osteoarthritis. Some neuropeptides appear trophic rather than catabolic, but very little definitive information prevails that can guide clinical practice safely and effectively. CONCLUSION: More research to tease out a distinctive role for neuropeptides in the context of articular cartilage destruction and/or repair is strongly indicated.

Th17 lymphocyte-dependent degradation of joint cartilage by synovial fibroblasts in a humanized mouse model of arthritis and reversal by secukinumab.

How T-helper (Th) lymphocyte subpopulations identified in synovial fluid from patients with juvenile idiopathic arthritis (JIA) (Th17, classic Th1, or nonclassic Th1) drive joint damage is of great interest for the possible use of biological drugs that inhibit the specific cytokines. Our objective was to clarify the role of such Th subpopulations in the pathogenesis of articular cartilage destruction by synovial fibroblasts (SFbs), and the effect of Th17 blockage in an animal model. SFbs were isolated from healthy subjects and patients with JIA, and peripheral blood Th lymphocytes subsets were obtained from healthy subjects. Fragments of human cartilage from healthy subjects in a collagen matrix containing JIA or normal SFbs grafted underskin in SCID mice were used to measure cartilage degradation under the effects of Th supernatants. JIA SFbs overexpress MMP9 and MMP2 and Th17 induce both MMPs in normal SFbs, while nonclassic Th1 upregulate urokinase plasminogen activator (uPA) activity. In vitro invasive phenotype of normal SFbs is stimulated with conditioned medium of Th17 and nonclassic-Th1. In the in vivo "inverse wrap" model, normal SFbs stimulated with supernatants of Th17-lymphocytes and nonclassic Th1 produced a cartilage invasion and degradation similar to JIA SFbs. Secukinumab inhibits the cartilage damage triggered by factors produced by Th17.

A Molecular Cascade Underlying Articular Cartilage Degeneration.

Preserving of articular cartilage is an effective way to protect synovial joints from becoming osteoarthritic (OA) joints. Understanding of the molecular basis of articular cartilage degeneration will provide valuable information in the effort to develop cartilage preserving drugs. There are currently no disease-modifying OA drugs (DMOADs) available to prevent articular cartilage destruction during the development of OA. Current drug treatments for OA focus on the reduction of joint pain, swelling, and inflammation at advanced stages of the disease. However, based on discoveries from several independent research laboratories and our laboratory in the past 15 to 20 years, we believe that we have a functional molecular understanding of articular cartilage degeneration. In this review article, we present and discuss experimental evidence to demonstrate a sequential chain of the molecular events underlying articular cartilage degeneration, which consists of transforming growth factor beta 1, high-temperature requirement A1 (a serine protease), discoidin domain receptor 2 (a cell surface receptor tyrosine kinase for native fibrillar collagens), and matrix metalloproteinase 13 (an extracellularmatrix degrading enzyme). If, as we strongly suspect, this molecular pathway is responsible for the initiation and acceleration of articular cartilage degeneration, which eventually leads to progressive joint failure, then these molecules may be ideal therapeutic targets for the development of DMOADs.

Relationship between Pain Behavior and Changes in KCNA2 Expression in the Dorsal Root Ganglia of Rats with Osteoarthritis

Objective. To investigate the relationship between pain behavior and potassium voltage-gated channel subfamily A member 2 (KCNA2) expression in dorsal root ganglia (DRGs) of rats with osteoarthritis (OA). Methods. Male Sprague-Dawley rats were randomly divided into three groups: blank control group (group C), normal saline group (group S), and group OA. Paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured one day before injection and one, two, four, and six weeks after injection. At one, two, four, and six weeks after injection, pathological knee joint changes and activated transcription factor-3 (ATF-3) and KCNA2 expressions in DRGs were analyzed. Results. Compared with preinjection, PWMT and PWTL at two, four, and six weeks after injection were significantly decreased in the group OA (P&lt;0.05 or 0.01). Compared with group C, PWMT and PWTL at two, four, and six weeks after injection were significantly decreased in the group OA (P&lt;0.05 or 0.01). In the group OA, slight local articular cartilage surface destruction was found at week one. The cartilage surface destruction gradually developed, and the exacerbation of cartilage matrix reduction and bone hyperplasia were increasingly aggravated and eventually evolved into advanced OA in the second to sixth weeks. Compared with group C, ATF-3 expression was significantly increased, and KCNA2 expression was significantly decreased in the group OA at two, four, and six weeks after injection (P&lt;0.05 or 0.01). Compared to baseline, ATF-3 expression was significantly increased, and KCNA2 expression was significantly decreased in the group OA (P&lt;0.05 or 0.01). Conclusion. Pain behavior in OA rats was associated with decreased KCNA2 expression in DRGs.

Depression and severity of articular destruction in patients with rheumatoid arthritis

To assess the influence of anxiety and depressive disorders on joint destruction in patients with rheumatoid arthritis (RA). 128 RA-patients were included, 87% were women with a mean age of 47.411.3 years and a median of RA duration 96 [48; 228] months. At the inclusion most patients had moderate (n=56, 43.7%) and severe (n=48, 37.5%) disease activity according to DAS28. Joint destruction was classified as maximal in patients with radiographic stage III, IV and/or osteonecrosis) and minimal in patients with stage I, II and no osteonecrosis. Pain intensity was measured with the BPI (Brief Pain Inventory) scale, severity of fatigue with fatigue severity scale (FSS), clinically important fatigue was diagnosed in patients with FSS4. Anxiety and depressive disorders (ADD) were diagnosed by a licensed psychiatrist in 123 (96.1%) of RA-patients in accordance with ICD-10 in semi-structured interview. Severity of depression and anxiety was evaluated with Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Anxiety Rating Scale (HAM-A). RA-patients with ADD were divided into the following treatment groups: 1 сDMARDs (n=39), 2 сDMARDs+PPT (sertraline or mianserine), n=43, 3 сDMARDs+bDMARDs (n=32), 4 сDMARDs+bDMARDs+PPT (sertraline or mianserine), n=9. Biologics treatment duration varied from 1 to 6 years, antidepressants from 6 to 96 weeks. 83 (67.5%) RA patients were assessed at five-years follow-up. Linear regression analysis was conducted to determine factors associated with maximal join destruction. According to linear regression analysis, maximal joint destruction at 5 years follow-up was associated with higher baseline BPImax, longer RA and ADD duration, clinically important fatigue at baseline, baseline extraarticular RA manifestations, recurrent depressive disorder at 5-years follow-up and treatment with cDMARDs only. Recurrent depressive disorder without antidepressant treatment is an important predictor of progression of joint destruction in patients with rheumatoid arthritis.

Characterization of the interleukin-17 effect on articular cartilage in a translational model: an explorative study

BackgroundOsteoarthritis (OA) is a progressive, chronic disease characterized by articular cartilage destruction. The pro-inflammatory cytokine IL-17 levels have been reported elevated in serum and synovial fluid of OA patients and correlated with increased cartilage defects and bone remodeling. The aim of this study was to characterize an IL-17-mediated articular cartilage degradation ex-vivo model and to investigate IL-17 effect on cartilage extracellular matrix protein turnover.MethodsFull-depth bovine femoral condyle articular cartilage explants were cultured in serum-free medium for three weeks in the absence, or presence of cytokines: IL-17A (100 ng/ml or 25 ng/ml), or 10 ng OSM combined with 20 ng/ml TNFα (O + T). RNA isolation and PCR analysis were performed on tissue lysates to confirm IL-17 receptor expression. GAG and ECM-turnover biomarker release into conditioned media was assessed with dimethyl methylene blue and ELISA assays, respectively. Gelatin zymography was used for matrix metalloproteinase (MMP) 2 and MMP9 activity assessment in conditioned media, and shotgun LC-MS/MS for identification and label-free quantification of proteins and protein fragments in conditioned media. Western blotting was used to validate MS results.ResultsIL-17RA mRNA was expressed in bovine full-depth articular cartilage and the treatment with IL-17A did not interfere with metabolic activity of the model. IL-17A induced cartilage breakdown; conditioned media GAG levels were 3.6-fold-elevated compared to untreated. IL-17A [100 ng/ml] induced ADAMTS-mediated aggrecan degradation fragment release (14-fold increase compared to untreated) and MMP-mediated type II collagen fragment release (6-fold-change compared to untreated). MS data analysis revealed 16 differentially expressed proteins in IL-17A conditioned media compared to untreated, and CHI3L1 upregulation in conditioned media in response to IL-17 was confirmed by Western blotting.ConclusionsWe showed that IL-17A has cartilage modulating potential. It induces collagen and aggrecan degradation indicating an upregulation of MMPs. This was confirmed by zymography and mass spectrometry data. We also showed that the expression of other cytokines is induced by IL-17A, which provide further insight to the pathways that are active in response to IL-17A. This exploratory study confirms that IL-17A may play a role in cartilage pathology and that the applied model may be a good tool to further investigate it.

Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF

BackgroundThe tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear.MethodsWe measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA.ResultsSoluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions.ConclusionsTL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.

Etoricoxib decreases subchondral bone mass and attenuates biomechanical properties at the early stage of osteoarthritis in a mouse model

Etoricoxib, a selective Cyclooxygenase-2 (COX-2) inhibitor, is commonly used in osteoarthritis (OA) for pain relief, however, little is known about the effects on subchondral bone. In the current study, OA was induced via destabilization of the medial meniscus (DMM) in C57BL/6 mice. Two days after surgery, mice were treated with different concentrations of Etoricoxib. Four weeks after treatment, micro computed tomography (Micro-CT) analysis, histological analysis, atomic force microscopy (AFM) analysis, and scanning electron microscopy (SEM) were performed to evaluate OA progression. We demonstrated that Etoricoxib inhibited osteophyte formation in the subchondral bone. However, it also reduced the bone volume fraction (BV/TV), lowered trabecular thickness (Tb.Th), and more microfractures and pores were observed in the subchondral bone. Moreover, Etoricoxib reduced the elastic modulus of subchondral bone. Exposure to Etoricoxib further increased the empty/total osteocyte ratio of the subchondral bone. Etoricoxib did not show significant improvement in articular cartilage destruction and synovial inflammation in early OA. Together, our observations suggested that although Etoricoxib can relieve OA-induced pain and inhibit osteophyte formation in the subchondral bone, it can also change the microstructures and biomechanical properties of subchondral bone, promote subchondral bone loss, and reduce subchondral bone quality in early OA mice.

Evaluation of Periarticular Pathology Surrounding Knee Joint Tissues in an Osteoarthritis Rat Model

Osteoarthritis (OA) is a multifactorial disease associated with pathological changes in a wide variety of musculoskeletal tissues, including articular cartilage degeneration, synovitis, ligament tears as well as muscle wasting. Cartilage is known as a predominant pathology, however the association between the pathogenesis of OA around the knee joint tissues and pain is limited. Infrapatellar fat pad (IFP) fibrosis and muscle atrophy are the main features of chronic OA phenomenon that cause joint pain, stiffness and impairment of skeletal muscle, which contributing to locomotor restriction in OA patients. Despite a high prevalence of knee OA, there is still a lack of comprehensive information explaining the interplaying mechanisms among these OA features. Although various animal models of OA have been characterized, none of them can truly represent all aspects of the OA features. Monoiodoacetate (MIA)‐induced OA is one of the most common animal model used in the OA research, in which intra‐articular injection of MIA can lead to articular cartilage destruction and development of pain‐like behaviour. This study aimed to characterize and determine the suitable time point, at which MIA could significantly induce the development of IFP fibrosis and hind limb muscle atrophy in this OA rat model. IFP and soleus muscle were collected for histological analysis at 4 and 8 weeks post‐OA induction. In addition, pain‐related behavior was also evaluated using hind limb weight distribution test. Semi‐quantitative analysis of Masson’s trichrome staining revealed that the percentage of IFP fibrosis area was not significantly different at 4 weeks compared to 8 weeks post‐OA induction. In addition, there was a significant (p&lt;0.05) reduction of soleus muscle fiber cross‐sectional area at 4 and 8 weeks of OA‐induced groups compared to their relative controls; however, the muscle fiber atrophy was more pronounced at 4 weeks compared to 8 weeks. Moreover, there was a significant reduction in the mean values of percent weight borne on the injured hind limb for the OA‐induced group compared to the saline group throughout the study period (p&lt;0.05). Interestingly, pain response significantly reversed at 8 weeks compared to 4 weeks (p&lt;0.001), suggesting that this reversal in pain response could be the contributing factor on alleviation of soleus muscle atrophy under chronic OA pain. These results suggested that at 4 weeks post‐MIA injection is sufficient and suitable period to investigate OA‐related pain, IFP fibrosis and muscle atrophy. Taken together, a MIA‐induced OA rat can be used as a representative model in translational research to understand IFP fibrosis and hind limb muscle atrophy in OA as an integrated musculoskeletal disease.

FlexPro MD®, a Combination of Krill Oil, Astaxanthin and Hyaluronic Acid, Reduces Pain Behavior and Inhibits Inflammatory Response in Monosodium Iodoacetate-Induced Osteoarthritis in Rats.

Osteoarthritis (OA) is a degenerative joint disease and a leading cause of adult disability. Since there is no cure for OA and no effective treatment to slow its progression, current pharmacologic treatments, such as analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), only alleviate symptoms, such as pain and inflammation, but do not inhibit the disease process. Moreover, chronic intake of these drugs may result in severe adverse effects. For these reasons, patients have turned to the use of various complementary and alternative approaches, including diverse dietary supplements and nutraceuticals, in an effort to improve symptoms and manage or slow disease progression. The present study was conducted to evaluate the anti-osteoarthritic effects of FlexPro MD® (a mixture of krill oil, astaxanthin, and hyaluronic acid; FP-MD) in a rat model of OA induced by monosodium iodoacetate (MIA). FP-MD significantly ameliorated joint pain and decreased the severity of articular cartilage destruction in rats that received oral supplementation for 7 days prior to MIA administration and for 21 days thereafter. Furthermore, FP-MD treatment significantly reduced serum levels of the articular cartilage degeneration biomarkers cartilage oligomeric matrix protein (COMP) and crosslinked C-telopeptide of type II collagen (CTX-II), and the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), as well as mRNA expression levels of inflammatory mediators, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and matrix-degrading enzymes, matrix metalloproteinase (MMP)-2 and MMP-9, in the knee joint tissue. Our findings suggest that FP-MD is a promising dietary supplement for reducing pain, minimizing cartilage damage, and improving functional status in OA, without the disadvantages of previous dietary supplements and medicinal agents, including multiple adverse effects.

LncRNA PVT1 induces chondrocyte apoptosis through upregulation of TNF-α in synoviocytes by sponging miR-211-3p

Temporomandibular joint osteoarthritis (TMJ OA) is an important subtype of temporomandibular disorders (TMD). Articular cartilage destruction is considered a common pathological feature of TMJ OA, which is reported to be mainly induced by chondrocyte apoptosis. Synovial sterile inflammation is an initial factor of TMJ OA-associated articular cartilage destruction. Therefore, determining the mechanism of synovial membrane inflammation-induced articular cartilage destruction in TMJ OA is important for the TMJ OA therapy. In this study, we detected the function of synoviocytes in chondrocyte apoptosis under lipopolysaccharide (LPS)-induced inflammatory conditions and explored the underlying mechanism. We found that synoviocytes in inflammatory conditions facilitated LPS-induced chondrocytes apoptosis by secreting increased Tumor Necrosis Factor α (TNF-α), which was induced by long non-coding RNA plasmacytoma variant translocation 1 (PVT1) upregulation. PVT1 served as a competing endogenous RNA that sponged the microRNA miR-211-3p and prevented the inhibition of TNF-α expression. In conclusion, our in vitro study revealed that PVT1 has a previously unknown role in chondrocyte apoptosis, which may also be a mechanism underlying synoviocyte involvement in TMJ OA.