Intra-articular hyaluronic acid in knee osteoarthritis: clinical data for a product family (ARTHRUM), with comparative meta-analyses.

INTRODUCTION: Viscosupplementation is widely practiced, to reduce pain in osteoarthritis (OA), using intra articular (IA) injections of hyaluronic acid (HA). In Europe, these products are class III medical devices, for which the Medical Device Regulation (MDR) requires clinical assessment, based on specific studies and/or a bibliographical review of equivalent devices. The purpose of this article is to present a comparative review between a family of devices (ARTHRUM, from LCA Pharmaceuticals, Chartres, France) and an extensive group of presumed equivalent IA HA devices or their controls, whose results have been published in Scientific journals. METHODS: To meet the criteria used in most ARTHRUM studies, the Western Ontario and McMaster Universities' index sub-scores were selected for pain (WOMAC A), stiffness (WOMAC B) and function (WOMAC C). The main criterion was the variation of the WOMAC A score from T0 (date of inclusion) to T6 (6 months). The other WOMAC criteria were assessed at T1, T3, T6 and complemented by OMERACT-OARSI rates of responders to the treatment. Fifty articles were selected, containing treatment details on more than 12,000 patients. These were divided into three groups: ARTHRUM, EQUIVALENTS and CONTROLS. To get quantitative comparisons, meta-analyses were performed for each criterion individually. The 95% confidence interval of each difference from baseline, was used to assess the clinical relevance, with reference to a minimum validated in OA literature. Comparisons between groups and tolerance assessment completed the investigation. RESULTS: For the WOMAC A, B and C scores, the full 95% CI was always above the minimal perceptible clinical improvement (MPCI), in the ARTHRUM and EQUIVALENTS groups, but not for all criteria in the CONTROLS group. In the comparisons, both ARTHRUM and EQUIVALENTS groups were significantly better than the CONTROLS group for each criterion. The effect size (ES) on pain, for the ARTHRUM and EQUIVALENTS groups, varied from 0.28 to 0.56 and from 0.23 to 0.27, respectively. Overall, ARTHRUM was estimated always non-inferior to EQUIVALENTS, and sometimes statistically and clinically superior. CONCLUSIONS: The comparison of ARTHRUM clinical studies, with studies selected through bibliographic research, leads to the conclusion that the clinical efficacy of the ARTHRUM medical devices, to reduce pain and improve the function in knee OA, during a six-month period, is at least as great as those of equivalent products. With good tolerance results (lowest rate of adverse events, and none of them serious), the risk benefit ratio favours using viscosupplementation with ARTHRUM.

Fraxetin inhibits interleukin-1ß-induced apoptosis, inflammation, and matrix degradation in chondrocytes and protects rat cartilage in vivo.

Osteoarthritis (OA) is a disease characterized by degeneration of the joint complex due to cartilage destruction. Fraxetin, a widely used and studied coumarin compound extracted from a traditional Chinese herb (Qin Pi), has shown anti-inflammatory and antioxidant properties, but its effects on OA have not been studied. In the present study, western blotting, immunofluorescence, and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) were used to evaluate the effects of fraxetin on IL-1ß-induced apoptotic activity, inflammatory responses, and catabolism in rat chondrocytes. The results showed that fraxetin prevented IL-1ß-induced apoptosis of chondrocytes and inhibited inflammatory mediator release by regulating the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor (NF)-κB pathway in chondrocytes. Additionally, fraxetin suppressed the upregulation of matrix metalloproteinase 13 (MMP13) and degradation of collagen II in the extracellular matrix (ECM). Moreover, the effects of fraxetin in vivo were assessed in a monosodium iodoacetate (MIA)-induced rat model of OA using hematoxylin and eosin (H&E) and Safranin O-fast green staining and magnetic resonance imaging (MRI). The results showed that fraxetin protected the cartilage against destruction. In conclusion, fraxetin could be a potential therapeutic for OA.

Magnetic resonance evaluation of knee osteoarthritis among the Saudi Population.

BACKGROUND AND OBJECTIVES: Osteoarthritis (OA) is the most prevalent worldwide joint degenerative disorder with high morbidities and disabilities. The current study aimed to investigate the prevalence of knee osteoarthritis (KOA) in Arar by using magnetic resonance imaging (MRI). METHODS: The prevalence of KOA was studied in Arar through MRI evaluation of randomly chosen sample from patients and their relatives attending the Prince Abdul Aziz Bin Mussad Hospital from October 2015 to November 2016. RESULTS: A total of 410 participants were enrolled in the study [328 (80%) male and 82 (20%) females]. After MRI, 163 participants [39.75% (95% CI) = 35.14 - 44.57%)] were diagnosed with KOA. The prevalence of OA was about 25.6% (95% CI = 20.8 - 31.1%) below the age of 40 years, which was found to increase by age in the enrolled volunteers. KOA prevalence was higher in females than males (75.6% and 27.7% respectively). There was a significant association between the age and genders of the participants and the prevalence of OA (p-value < 0.0001 for both variables). There was also a significant association between the age and gender of the participants and the MRI-estimated grading (p-value < 0.0001 and 0.0044 respectively). CONCLUSION: KOA is a common disease among Arar young population, especially females. Its prevalence increases by age with higher grades of severity affecting the elderly.

Vitamin D supplementation and inflammatory and metabolic biomarkers in patients with knee osteoarthritis: post hoc analysis of a randomised controlled trial.

The aim of this study was to determine whether vitamin D supplementation and maintaining vitamin D sufficiency are associated with changes in inflammatory and metabolic biomarkers in patients with knee osteoarthritis (OA) and vitamin D deficiency. A total of 413 participants with symptomatic knee OA and vitamin D deficiency were enrolled in a randomised, placebo-controlled trial and received 1·25 mg vitamin D3 or placebo monthly for 24 months across two sites. In this post hoc analysis, 200 participants from one site (ninety-four from the placebo group and 106 from the vitamin D group; mean age 63·1 (sd 7·3) years, 53·3 % women) were randomly selected for measurement of serum levels of inflammatory and metabolic biomarkers at baseline and 24 months using immunoassays. In addition, participants were classified into two groups according to serum 25-hydroxyvitamin D (25(OH)D) levels at months 3 and 24: (1) not consistently sufficient (25(OH)D≤50 nmol/l at either month 3 or 24, n 61), and (2) consistently sufficient (25(OH)D>50 nmol/l at both months 3 and 24, n 139). Compared with placebo, vitamin D supplementation had no significant effect on change in serum high-sensitive C-reactive protein, IL-6, IL-8, IL-10, leptin, adiponectin, resistin, adipsin and apelin. Being consistently vitamin D sufficient over 2 years was also not associated with changes in these biomarkers compared with not being consistently sufficient. Vitamin D supplementation and maintaining vitamin D sufficiency did not alter serum levels of inflammatory and metabolic biomarkers over 2 years in knee OA patients who were vitamin D insufficient, suggesting that they may not affect systemic inflammation in knee OA patients.

Prenatal food restriction induces poor-quality articular cartilage in female rat offspring fed a post-weaning high-fat diet and its intra-uterine programming mechanisms.

Epidemiological data show that osteoarthritis (OA) is significantly associated with lower birth weight, and that OA may be a type of fetal-originated adult disease. The present study aimed to investigate the prenatal food-restriction (PFR) effect on the quality of articular cartilage in female offspring to explore the underlying mechanisms of fetal-originated OA. Maternal rats were fed a restricted diet from gestational day (GD) 11 to 20 to induce intra-uterine growth retardation. Female fetuses and female adult offspring fed a post-weaning high-fat diet were killed at GD20 and postnatal week 24, respectively. Serum and knee cartilage samples from fetuses and adult female offspring were collected and examined for cholesterol metabolism and histology. Fetal serum corticosterone and insulin-like growth factor-1 (IGF-1) in the PFR group were lower than those of the control, but the serum cholesterol level was not changed. The lower expression of IGF-1 in the PFR group lasted into adulthood. The expression of extracellular matrix (ECM) genes, including type II collagen, aggrecan and cholesterol efflux genes including liver X receptor, were significantly induced, but the ATP-binding-cassette transporter A1 was unchanged. PFR could induce a reduction in ECM synthesis and impaired cholesterol efflux in female offspring, and eventually led to poor quality of articular cartilage and OA.

Effects of sodium selenite on c-Jun N-terminal kinase signalling pathway induced by oxidative stress in human chondrocytes and c-Jun N-terminal kinase expression in patients with Kashin-Beck disease, an endemic osteoarthritis.

The c-Jun N-terminal kinases (JNK) are members of the mitogen-activated protein kinase family and are activated by environmental stress. Se plays an important role in the biological pathways by forming selenoprotein. Selenoproteins have been shown to exhibit a variety of biological functions including antioxidant functions and maintaining cellular redox balance, and compromise of such important proteins would lead to oxidative stress and apoptosis. We examined the expression levels of JNK in Kashin-Beck disease (KBD) patients, tested the potential protective effects of sodium selenite on tert-butyl hydroperoxide (tBHP)-induced oxidative injury and apoptosis in human chondrocytes as well as its underlying mechanism in this study. We produced an oxidative damage model induced by tBHP in C28/I2 human chondrocytes to test the essential anti-apoptosis effects of Se in vitro. The results indicated that the expression level of phosphorylated JNK was significantly increased in KBD patients. Cell apoptosis was increased and molecule expressions of the JNK signalling pathway were activated in the tBHP-injured chondrocytes. Na2SeO3 protected against tBHP-induced oxidative stress and apoptosis in cells by increasing cell viability, reducing reactive oxygen species generation, increasing Glutathione peroxidase (GPx) activity and down-regulating the JNK pathway. These results demonstrate that apoptosis induced by tBHP in chondrocytes might be mediated via up-regulation of the JNK pathway; Na2SeO3 has an effect of anti-apoptosis by down-regulating the JNK signalling pathway.

Arthroscopic knee debridement in osteoarthritis in the older age can be satisfactory.

Introduction: Knee arthroscopy is one of the treatments for knee pain. In recent years, the use of knee arthroscopy in the treatment of osteoarthritis was challenged by several randomized-controlled trials, systematic reviews and meta-analyses. However, some design flaws are making the clinical decision harder. This study specifically explores the patient satisfaction from these surgeries to aid in clinical decision. Hypothesis: Knee arthroscopy can relieve symptoms and delay further surgical treatment in the older age. Patients & methods: Fifty patients accepted participation and were invited to a follow-up examination eight years post knee arthroscopy. All patients were above age 45 and diagnosed with degenerative meniscus tear and osteoarthritis. The patients filled follow-up questionnaires of function (WOMAC, IKDC, SF-12) and pain. The patients were asked to appreciate if they would have repeated the surgery retrospectively. The results were compared to a previous data base. Results: Thirty-six patients (72%) reported satisfaction of 8 and above (scale of 0-10) from the surgery and would have repeated it. A higher SF-12 physical score pre-surgery predicted a higher satisfaction rate (p = 0.027). Patients who were more satisfied from the surgery improved post-surgery in all parameters compared with the less-satisfied group (p < 0.001). Patients above the age 60 had similar parameters pre- and post-surgery compared with patients under the age 60 (p > 0.05). Conclusions: Patients between the ages 46-78 with degenerative meniscus tear and osteoarthritis felt they benefited from knee arthroscopy in an eight-year follow-up and would repeat the surgery. Our research may help with better patient selection and suggest knee arthroscopy can relive symptoms and delayed further surgical treatment for the older patient with clinical symptoms and signs of meniscus related pain, mild osteoarthritis, and failed conservative treatment. Level of evidence: IV.

Radiographically detectable intra-articular mineralization: Predictor of knee osteoarthritis outcomes or only an indicator of aging? A brief report from the osteoarthritis initiative.

Objective: To determine the association between Intra-articular mineralization (IAM) and knee osteoarthritis (OA) outcomes stratified according to participants' age. Methods: Participants from the Osteoarthritis Initiative (OAI) with baseline radiographic OA (i.e., Kellgren-Lawrence grade ≥2 with Osteoarthritis Research Society International (OARSI) atlas joint space narrowing (JSN)) in either knee were identified. Both knees and dominant hand baseline radiographs were evaluated for the presence of IAM. Whole-grade OARSI-JSN radiographic progression and increased Western Ontario and McMaster universities osteoarthritis index scores of the knees with baseline radiographic OA (assessed annually) were defined as radiographic and symptomatic progression, respectively. Cox proportional-hazards and longitudinal multilevel regression models investigated radiographic and symptomatic progression, respectively. Results: 2010 participants with baseline radiographic OA in either one or both knees (N â€‹= â€‹2976) were identified. 178 participants had baseline IAM (hand radiographs â€‹= â€‹46, knee radiographs â€‹= â€‹166, both â€‹= â€‹34). An adjusted logistic regression model suggests an association between age and IAM (Odds Ratio: 1.06, 95% Confidence Interval (CI): 1.04-1.08). Presence of any IAM was not associated with whole-grade OARSI-JSN (Hazard Ratio (HR): 1.00, 95% CI: 0.73-1.37) or symptomatic progression (Estimated difference: 1.24, p-value: 0.13) in all participants. Using stratification analysis, in younger participants <60 years old, presence of any IAM was associated with radiographic progression (HR: 1.90, 95% CI: 1.01-3.60). Conclusion: Although the presence of any radiographic IAM increases with higher age and does not predict knee OA outcomes across the entire sample of OAI participants, it is associated with knee OA radiographic progression in participants aged <60.

A static magnetic field enhances the repair of osteoarthritic cartilage by promoting the migration of stem cells and chondrogenesis.

Objective: To investigate the therapeutic effects of static magnetic field (SMF) and its regulatory mechanism in the repair of osteoarthritic cartilage. Methods: Fourteen-week-old female C57BL/6 mice were randomly divided into the sham operation group and the osteoarthritis (OA) groups with and without SMF application. SMF was applied at 200 â€‹mT for two consecutive weeks. Changes in knee cartilage were examined by histomorphometry, and the chondrogenesis and migration of endogenous stem cells were assessed. The expression of SRY-related protein 9 (SOX9), Collagen type II (COL2), matrix metallopeptidase 13 (MMP13), stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4), Piezo1 and other genes was evaluated, and the mechanism of SMF's action was tested using the CXCR4 inhibitor, AMD3100, and Piezo1 siRNA. Results: SMF significantly decreased the OARSI scores after induction of OA. SMF was beneficial to chondrogenesis by elevating SOX9. In the OA mouse model, an increase in MMP13 with a decrease in COL2 led to the destruction of the cartilage extracellular matrix, which was suppressed by SMF. SMF promoted the migration of cartilage-derived stem/progenitor cells and bone marrow-derived mesenchymal stem cells (MSCs). It increased SDF-1 and CXCR4, while the CXCR4 inhibitor significantly suppressed the beneficial effects of SMF. The application of Piezo1 siRNA inhibited the SMF-induced increase of CXCR4. Conclusion: SMF enhanced chondrogenesis and improved cartilage extracellular matrices. It activated the Piezo1-mediated SDF-1/CXCR4 regulatory axis and promoted the migration of endogenous stem cells. Collectively, it attenuated the pathological progression of cartilage destruction in OA mice. The Translational potential of this article: The findings in this study provided convincing evidence that SMF could enhance cartilage repair and improve OA symptoms, suggesting that SMF could have clinical value in the treatment of OA.

Sexual dimorphism in knee osteoarthritis: Biomechanical variances and biological influences.

Objective: Osteoarthritis (OA) is a degenerative joint disease that is more prevalent in women than men, especially later in life. This suggests that sexual dimorphism may be present in the pathogenesis of the disease. The purpose of this review is to discuss evidence of sexual dimorphism in knee OA development and presentation as it is framed by two contrasting paradigms: biomechanics and biology. Methods: A comprehensive search of databases was conducted including, but not limited to, MEDLINE via Ovid, PubMed, and Google Scholar. Keywords including osteoarthritis, sex differences, and/or sexual dimorphism were searched in combination with knee biomechanics, ACL, joint malalignment, estrogen, chondrocyte signal(l)ing, growth factor and integrin(s). Results: The biomechanical approach has identified sex differences in joint malalignment, bone shape, gait, and lower limb muscle strength leading to altered load transmission, as well as increased knee laxity in women predisposing them to joint injury. The biological approach has largely focused on the influence of estrogen receptor signaling on the maintenance of joint tissues. Preliminary work identifying sexual dimorphism in chondrocyte signaling pathways involving growth factors and collagen receptors has been reported in addition to more systemic levels of inflammatory cytokines and metabolites. Conclusion: Understanding the true etiology of OA is crucial for developing effective, individualized treatment in the age of personalised medicine. A shift from a 'one size fits all' mentality towards an individualized approach for therapeutic treatment must begin with the acknowledgment of sex differences in the biomechanical and biological factors underlying the onset and development of OA.

What do patients want out of their Total Knee Arthroplasty?: An Indian perspective.

INTRODUCTION AND AIM: Total Knee Arthroplasty surgery is one of the most successful operations in orthopaedics. Still a sizable percentage of patients remain dissatisfied. Various studies have been conducted to analyse the red flags associated with poor outcome. In this study we tried to have insight on actual requirements of Indian patients from TKA operation. MATERIAL & METHODS: 300 patients undergoing TKA were studied by way of patient expectation feedback form. The form had various patient related capture points. It had a leading question: What are your expectations from TKA? They were asked to rank the 5 most important options in the order of importance. The patient expectation form was distributed and collected by an independent observer. RESULTS: 70% of patients ranked relief of pain as the most important expectation. 20% reported improvement in walking as the number one expectation. Nearly equal number listed improvement in walking and ease of doing day-to-day activities as the second most important expectation. This was followed by improvement in climbing the stairs and improvement in quality of life. Correction of deformity and no pain while squatting and getting up from sitting position ranked at the bottom. CONCLUSION: Our study shows that the primary expectations of Indian population from their TKA are relief from pain and improvement in walking. Secondary expectations include ease of doing day-to-day activities and improvement in quality of life.

A two-stage digestion of whole murine knee joints for single-cell RNA sequencing.

Objective: Single-cell RNA sequencing (scRNA-seq) is a powerful technology that can be applied to the cells populating the whole knee in the study of joint pathology. The knee contains cells embedded in hard structural tissues, cells in softer tissues and membranes, and immune cells. This creates a technical challenge in preparing a viable and representative cell suspension suitable for use in scRNA-seq in minimal time, where under-digestion may exclude cells in hard tissues, over-digestion may damage soft tissue cells, and prolonged digestion may induce phenotypic drift. We developed a rapid two-stage digestion protocol to overcome these difficulties. Design: A two-stage digest consisting of first collagenase IV, an intermediate cell recovery, then collagenase II on the remaining hard tissue. Cells were sequenced on the 10x Genomics platform. Results: We observed consistent cell numbers and viable single cell suspensions suitable for scRNA-seq analysis. Comparison of contralateral knees and separate mice showed reproducible cell yields and gene expression patterns by similar cell-types. A diverse collection of structural and immune cells were captured with a majority from immune origins. Two digestions were necessary to capture all cell-types. Conclusions: The knee contains a diverse mixture of stromal and immune cells that may be crucial for the study of osteoarthritis. The two-stage digestion presented here reproducibly generated highly viable and representative single-cell suspension for sequencing from the whole knee. This protocol facilitates transcriptomic studies of the joint as a complete organ.

Non-homologous use of adipose-derived cell and tissue therapies: Osteoarthritis as a case study.

Adipose tissue is widely recognized as an abundant and accessible human tissue that serves as a source of cells and extracellular matrix scaffolds for regenerative surgical applications. Increasingly, orthopedic surgeons are turning to adipose tissue as a resource in their treatment of osteoarthritis and related conditions. In the U.S., the regulatory landscape governing the orthopedic surgical utilization of autologous and allogeneic adipose tissue remains complex. This manuscript reviews the Food and Drug Administration's nomenclature and guidance regarding adipose tissue products. Additionally, it surveys recent pre-clinical and clinical trial literature relating to the application of adipose-derived cells and tissues in the treatment of osteoarthritis.

Do people with knee osteoarthritis use guideline-consistent treatments after an orthopaedic surgeon recommends nonsurgical care? A cross-sectional survey with long-term follow-up.

Objective: Describe "usual care" patterns of education, exercise, weight management, pain medication and other nonsurgical treatments for knee osteoarthritis (OA) in people recommended for nonsurgical care by an orthopaedic surgeon. Methods: We used a telephone-administered questionnaire to capture treatments people with knee OA used over the three to six years after an orthopaedic surgeon recommended nonsurgical care. The primary outcome, guideline-consistent nonsurgical treatments, was an aggregate measure defined as using education, exercise, weight management, and at least one recommended medication. Secondary outcomes were first-line (education, exercise, and weight management) and guideline-inconsistent treatments (orthoses, opioids, hyaluronic acid, platelet rich plasma, and stem cell therapy). Multivariable robust Poisson regression assessed the association between participant characteristics and use of guideline-consistent, first-line and guideline-inconsistent treatments. Results: 479 people were invited and 250 participated (52%). Participants were 58% female with a mean age 66.2 years. Participants received education by a healthcare professional (64%), exercised regularly (74%), used weight management (38%), and used recommended pain medications (91%). All guideline-consistent nonsurgical treatments were used by 19% of participants, 19% of participants used first-line treatments, and 42% used guideline-inconsistent treatments. Over six years, 34% had another consult then underwent arthroplasty. Older participants were less likely to use any treatment. People without post-secondary education were less likely to use first-line treatments (RR 0.54, 95% CI: 0.30-0.96), and females were less likely to use guideline-inconsistent treatments (RR 0.62, 95% CI:0.47-0.81). Conclusions: Nonsurgical usual care for people with knee OA was not consistent with international clinical guidelines.

Osteoarthritis Data Integration Portal (OsteoDIP): A web-based gene and non-coding RNA expression database.

Objective: OsteoDIP aims to collect and provide, in a simple searchable format, curated high throughput RNA expression data related to osteoarthritis. Design: Datasets are collected annually by searching "osteoarthritis gene expression profile" in PubMed. Only publications containing patient data and a list of differentially expressed genes are considered. From 2020, the search has expanded to include non-coding RNAs. Moreover, a search in GEO for "osteoarthritis" datasets has been performed using 'Homo sapiens' and 'Expression profiling by array' filters. Annotations for genes linked to osteoarthritis have been downloaded from external databases. Results: Out of 1204 curated papers, 63 have been included in OsteoDIP, while GEO curation led to the collection of 28 datasets. Literature data provides a snapshot of osteoarthritis research derived from 1924 human samples, while GEO datasets provide expression for additional 1012 patients. Similar to osteoarthritis literature, OsteoDIP data has been created mostly from studies focused on knee, and the tissue most frequently investigated is cartilage. GEO data sets were fully integrated with associated clinical data. We showcase examples and use cases applicable for translational research in osteoarthritis. Conclusions: OsteoDIP is publicly available at http://ophid.utoronto.ca/OsteoDIP. The website is easy to navigate and all the data is available for download. Data consolidation allows researchers to perform comparisons across studies and to combine data from different datasets. Our examples show how OsteoDIP can integrate with and improve osteoarthritis researchers' pipelines.

Comparison of the yields and properties of dedifferentiated fat cells and mesenchymal stem cells derived from infrapatellar fat pads.

Introduction: Infrapatellar fat pad (IFP)-derived mesenchymal stem cells (MSCs) have high chondrogenic potential and are attractive cell sources for cartilage regeneration. During ceiling culture to acquire the characteristics of MSCs, mature adipocytes from fat tissue are known to undergo dedifferentiation, generating dedifferentiated fat (DFAT) cells. The purpose of the present study was to compare the yields and biological properties of IFP-derived MSCs and IFP-derived DFAT cells. Methods: IFPs were harvested from the knees of 8 osteoarthritis (OA) patients. DFAT cells were obtained using a ceiling culture of adipocytes isolated from the floating top layer of IFP digestion. MSCs were obtained by culturing precipitated stromal vascular fraction cells. We compared the P0 cell yields, surface antigen profile, colony formation ability, and multipotency of DFAT cells and MSCs. Results: The P0 cell yields per flask and the estimated total cell yields from 1 g of IFP were much greater for MSCs than for DFAT cells. Both MSCs and DFAT cells were positive for MSC markers. No obvious difference was observed in colony formation ability. In differentiation assays, DFAT cells produced greater amounts of lipid droplets, calcified tissue, and glycosaminoglycan than MSCs did. Adipogenic and chondrogenic gene expressions were upregulated in DFAT cells. Conclusions: IFP-derived DFAT cells showed higher adipogenic and chondrogenic potentials than IFP-derived MSCs, but they had a poor cell yield.

Long non-coding RNA HCAR promotes endochondral bone repair by upregulating VEGF and MMP13 in hypertrophic chondrocyte through sponging miR-15b-5p.

Endochondral bone formation is an important route for bone repair. Although emerging evidence has revealed the functions of long non-coding RNAs (lncRNAs) in bone and cartilage development, the effect of lncRNAs in endochondral bone repair is still largely unknown. Here, we identified a lncRNA, named Hypertrophic Chondrocyte Angiogenesis-related lncRNA (HCAR), and proved it to promote the endochondral bone repair by upregulating the expression of matrix metallopeptidase 13 (Mmp13) and vascular endothelial growth factor α (Vegfa) in hypertrophic chondrocytes. Lnc-HCAR knockdown in hypertrophic chondrocytes restrained the cartilage matrix remodeling and decrease the CD31hiEmcnhi vessels number in a bone repair model. Mechanistically, we proved that lnc-HCAR was mainly enriched in the cytoplasm using fluorescence in situ hybridization (FISH) assay, and it acted as a molecular sponge for miR-15b-5p. Further, in hypertrophic chondrocytes, lnc-HCAR competitively bound to miR-15b-5p to increase Vegfa and Mmp13 expression. Our results proved that lncRNA is deeply involved in endochondral bone repair, which will provide a new theoretical basis for future strategies for promoting fracture healing.

YY1-induced lncRNA XIST inhibits cartilage differentiation of BMSCs by binding with TAF15 to stabilizing FUT1 expression.

Introduction: The functional roles and mechanism of the XIST in osteoarthritis and the chondrogenic differentiation of BMSCs were clarified. Methods: The expression levels of XIST, TAF15, FUT1 and YY1 were detected through quantitative RT-PCR. The protein expression of Sox9, ACAN, COL2A1 and FUT1 were detected by western blot and immunohistochemistry. The damage of cartilage tissue was detected by HE staining, and Safranin O-fast green. Alcian-Blue and Alizarin red S staining were performed to evaluate BMSCs chondrogenic differentiation. The relationship between XIST and TAF15, XIST and TAF15 were analyzed by RNA immunoprecipitation assay. Luciferase reporter assays and chromatin immunoprecipitation were performed to detect the interaction relationship between XIST and YY1. In addition, osteoarthritis mice were built to assess the function of XIST in vivo. Results: The levels of XIST, TAF15 and FUT1 were upregulated in cartilage tissues from osteoarthritis patient. The level of XIST was decreased in BMSCs during chondrogenic differentiation. XIST overexpression inhibited the chondrogenic differentiation of BMSCs. Moreover, silencing of FUT1 reversed the effects of XIST overexpression on BMSCs chondrogenic differentiation. Mechanistically, in BMSCs, YY1 induced the expression of XIST in BMSCs, and XIST regulated FUT1 mRNA stability through targeting TAF15. Furthermore, silencing of XIST alleviated the symptoms of cartilage injury in OA mice. Conclusion: Taken together, these results suggested that YY1 induced XIST was closely related to the chondrogenic differentiation of BMSCs and the progression of osteoarthritis by TAF15/FUT1 axis, and may be a new OA therapeutic target.

Feasibility of the SOAR (Stop OsteoARthritis) program.

Objective: Assess the feasibility of a virtually-delivered, physiotherapist-guided knee health program (SOAR) that targets self-management of knee health and osteoarthritis risk after an activity-related knee injury. Design: In this quasi-experimental feasibility study, individuals with varied lived experience of knee trauma completed a 4-week SOAR program. This included: 1) Knee Camp (group education, 1:1 exercise and activity goal-setting); 2) weekly home-based exercise and activity program with tracking, and; 3) weekly 1:1 physiotherapy-guided action-planning. SOAR program feasibility was assessed with implementation (attrition, adherence, intervention fidelity), practicality (adverse events, goal completion), acceptability and efficacy (change in Knee injury and Osteoarthritis Outcome Score subscales, Patient Specific Functional Scale (PSFS), Godin Leisure-Time Exercise Questionnaire (GLTEQ), Partner in Health Scale (PHS)) outcomes. Descriptive statistics, disaggregated by gender, were calculated. Results: Thirty participants (60% women, median (min-max) age 30 years (19-50), time from injury 5.6 years (1.2-25.2)) were enrolled. No participant attrition or adverse events were reported, and 90% of mandatory program components were completed. Participants rated their adherence at 80%, and 96% of exercise-therapy and 95% of activity goals were fully or partially achieved. Both women and men reported significant group mean (95%CI) improvements in GLTEQ scores (women: 22 METS (6,37), men: 31 METS (8,54)), while women alone reported improvements in PHS (-7 (-11,-3) and PSFS (1.7 (0.6,2.8) scores. Conclusion: The SOAR program is feasible for persons at various timepoints post-knee trauma, and gender may be an important consideration for SOAR implementation and assessment. A randomized controlled trial to assess intervention efficacy is warranted.

Interventions for osteoarthritis pain: A systematic review with network meta-analysis of existing Cochrane reviews.

Objective: To conduct a network meta-analysis comparing all treatments for osteoarthritis (OA) pain in the Cochrane Library. Design: The Cochrane Library and Epistemonikos were searched for randomized controlled trials (RCTs) about treatments for hip and knee OA. We constructed 17 broad categories, comprising drug treatments, exercise, surgery, herbs, orthotics, passive treatments, regenerative medicine, diet/weight loss, combined treatments, and controls. In addition to a full network analysis, we compared the direct/indirect effects, and studies with shorter-/longer follow-up. CINeMA software was used for assessing confidence in network meta-analysis estimates. Results: We included 35 systematic reviews including 445 RCTs. There were 153 treatments for OA. In total, 491 comparisons were related to knee OA, less on hip OA, and only nine on hand OA. Six treatment categories showed clinically significant effects favoring treatment over control on pain. "Diet/weight loss" and "Surgery" had effect sizes close to zero. The network as a whole was not coherent. Of 136 treatment comparisons, none were rated as high confidence, six as moderate, 13 as low, and 117 as very low. Conclusions: Direct comparison of different available treatment options for OA is desirable, however not currently feasible in practice, due to heterogeneous study populations and lack of clear descriptions of control interventions. We found that many treatments were effective, but since the network as a whole was not coherent and lacked high confidence in the treatment comparisons, we could not produce a ranking of effects.