Search

Objectives: Early-onset osteoarthritis (OA) is an emerging health issue amidst the escalating prevalence of overweight and obesity. However, there are scant data on its disease, economic burden and attributable burden due to high body mass index (BMI)., Methods: Using data from the Global Burden of Diseases Study 2019, we examined the numbers of incident cases, prevalent cases, years lived with disability (YLDs) and corresponding age-standardised rates for early-onset OA (diagnosis before age 55) from 1990 to 2019. The case definition was symptomatic and radiographically confirmed OA in any joint. The average annual percentage changes (AAPCs) of the age-standardised rates were calculated to quantify changes. We estimated the economic burden of early-onset OA and attributable burden to high BMI., Results: From 1990 to 2019, the global incident cases, prevalent cases and YLDs of early-onset OA were doubled. 52.31% of incident OA cases in 2019 were under 55 years. The age-standardised rates of incidence, prevalence and YLDs increased globally and for countries in all Sociodemographic Index (SDI) quintiles (all AAPCs>0, p<0.05), with the fastest increases in low-middle SDI countries. 98.04% of countries exhibited increasing trends in all age-standardised rates. Early-onset OA accounts for US$46.17 billion in healthcare expenditure and US$60.70 billion in productivity loss cost in 2019. The attributable proportion of high BMI for early-onset OA increased globally from 9.41% (1990) to 15.29% (2019)., Conclusions: Early-onset OA is a developing global health problem, causing substantial economic costs in most countries. Targeted implementation of cost-effective policies and preventive intervention is required to address the growing health challenge., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: Synovial abnormalities are modifiable targets for hand pain and osteoarthritis. We examined the prevalence and distribution of ultrasound-detected hand synovial abnormalities in a community-derived sample of older people in China., Methods: Within the Xiangya Osteoarthritis Study, a community-based study, we assessed synovial hypertrophy (SH), joint effusion, and Power Doppler signal (PDS) on all fingers and thumbs of both hands using standardized ultrasound examinations (score: 0-3). We assessed distribution patterns of SH and effusion using χ2-test and interrelationships of SH and effusion in different joints and hands by generalized estimating equations., Results: Among 3,623 participants (mean age: 64.4 years; women: 58.1%), prevalence of SH, effusion and PDS were 85.5%, 87.3% and 1.5%, respectively. Prevalence of SH, effusion and PDS increased with age, was higher in the right hand than in the left hand and was more common in proximal than in distal hand joints. SH and effusion often occurred in multiple joints (P < 0.001). SH in one joint was strongly associated with presence of SH in the same joint of the opposite hand (odds ratio [OR]= 6.60, 95% confidence interval [CI]: 6.19-7.03) followed by SH in other joints in the same row, (OR=5.70, 95%CI: 5.32-6.11), and then other joints in the same ray of the same hand (OR=1.49, 95%CI: 1.39-1.60). Similar patterns were observed for effusion., Conclusion: Hand synovial abnormalities are common among older people, often affect multiple hand joints and present a unique pattern. These findings suggest both systemic and mechanical factors play roles in their occurrence., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Since gut microbiome dysbiosis can cause inflammatory disorders by affecting host metabolism, we postulate that the gut microbiome and related metabolites could play a role in hand osteoarthritis. We characterised gut microbiome-related metabolites in people with symptomatic hand osteoarthritis (SHOA) in two independent cohorts., Methods: Using data collected from a large-sample community-based observational study (discovery cohort), we assessed the relations of the microbial function and plasma key metabolites related to altered microbial function with SHOA. Finally, we verified the relations of plasma metabolites to SHOA in an independent observational study (validation cohort)., Findings: In the discovery cohort (n = 1359), compared to those without SHOA, participants with SHOA had significantly altered microbial functions related to tryptophan metabolism (Q = 0.025). Therefore we measured the plasma tryptophan metabolites and found that participants with SHOA had higher levels of 5-hydroxyindoleacetic acid (odds ratio [OR] = 1.25, 95% confidence interval [CI]: 1.09-1.42) and 5-hydroxytryptophol (OR = 1.13, 95% CI: 1.04-1.23), but lower levels of indole-3-lactic acid (ILA) (OR = 0.85, 95% CI: 0.72-1.00), skatole (OR = 0.93, 95% CI: 0.88-0.99) and 3-hydroxyanthranilic acid (OR = 0.90, 95% CI: 0.85-0.96). Findings from the validation cohort (n = 142) verified that lower levels of ILA were related to SHOA (OR = 0.70, 95% CI: 0.53-0.92)., Interpretation: Alterations of the microbial function of tryptophan biosynthesis and tryptophan metabolites, especially lower levels of ILA, are associated with SHOA. These findings suggest the role of the microbiome and tryptophan metabolites in developing of SHOA and may contribute to future translational opportunities., Funding: National Key Research and Development Plan and National Natural Science Foundation of China., Competing Interests: Declaration of interests All authors have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The pathogenesis of hand osteoarthritis (OA) remains unknown. Hyperuricaemia, which is related to inflammation, may play a role in hand OA, but evidence is lacking. In a large population-based study, we examined the association between hyperuricaemia and hand OA., Methods: Participants were from the Xiangya OA Study, a community-based observational study. Hyperuricaemia was defined as serum urate >416 µmol/L in men and >357 µmol/L in women. Radiographic hand OA (RHOA) was defined as presence of the modified Kellgren-Lawrence grade ≥2 in any hand joint. Symptomatic hand OA (SHOA) was defined as presence of both self-reported symptoms and RHOA in the same hand. The associations of hyperuricaemia with RHOA or SHOA were examined using generalised estimating equations., Results: Among 3628 participants, the prevalence of RHOA was higher in participants with hyperuricaemia than those with normouricaemia (26.9% vs 20.9%), with an adjusted OR (aOR) of 1.34 (95% CI 1.11 to 1.61). The associations were consistent in men (aOR 1.33, 95% CI 1.01 to 1.74) and women (aOR 1.35, 95% CI 1.05 to 1.74). Hyperuricaemia was mainly associated with bilateral RHOA (aOR 1.54, 95% CI 1.18 to 2.01) but not unilateral RHOA (aOR 1.13, 95% CI 0.89 to 1.45). Prevalence of SHOA was higher, although statistically insignificant, in participants with hyperuricaemia (aOR 1.39, 95% CI 0.94 to 2.07)., Conclusion: In this population-based study, hyperuricaemia was associated with a higher prevalence of hand OA. Future prospective studies are required to investigate the temporal relationship., Trial Registration Number: NCT04033757., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hand osteoarthritis is a common heterogeneous joint disorder with unclear molecular mechanisms and no disease-modifying drugs. In this study, we performed single-cell RNA sequencing analysis to compare the cellular composition and subpopulation-specific gene expression between cartilage with macroscopically confirmed osteoarthritis (n = 5) and cartilage without osteoarthritis (n = 5) from the interphalangeal joints of five donors. Of 105 142 cells, we identified 13 subpopulations, including a novel subpopulation with inflammation-modulating potential annotated as inflammatory chondrocytes. Fibrocartilage chondrocytes exhibited extensive alteration of gene expression patterns in osteoarthritic cartilage compared with nonosteoarthritic cartilage. Both inflammatory chondrocytes and fibrocartilage chondrocytes showed a trend toward increased numbers in osteoarthritic cartilage. In these two subpopulations from osteoarthritic cartilage, the ferroptosis pathway was enriched, and expression of iron overload-related genes, e.g., FTH1, was elevated. To verify these findings, we conducted a Mendelian randomization study using UK Biobank and a population-based cross-sectional study using data collected from Xiangya Osteoarthritis Study. Genetic predisposition toward higher expression of FTH1 mRNA significantly increased the risk of hand osteoarthritis (odds ratio = 1.07, 95% confidence interval: 1.02-1.11) among participants (n = 332 668) in UK Biobank. High levels of serum ferritin (encoded by FTH1), a biomarker of body iron overload, were significantly associated with a high prevalence of hand osteoarthritis among participants (n = 1 241) of Xiangya Osteoarthritis Study (P-for-trend = 0.037). In conclusion, our findings indicate that inflammatory and fibrocartilage chondrocytes are key subpopulations and that ferroptosis may be a key pathway in hand osteoarthritis, providing new insights into the pathophysiology and potential therapeutic targets of hand osteoarthritis., (© 2023. The Author(s).)

Nonsteroidal antiinf lammatory drugs (NSAIDs) remain the mainstay of the pharmacologic management for relieving osteoarthritis pain, and low-dose aspirin is often prescribed to osteoarthritis patients who are at high risk of cardiovascular disease (CVD). We conducted cohort studies using data from The Health Improvement Network (THIN) database (2000-2019) to assess whether the relationship of initiation of naproxen or ibuprofen vs. initiation of other NSAIDs (excluding both naproxen and ibuprofen), respectively, to the risk of CVD was modified by coprescription of low-dose aspirin among the participants with osteoarthritis. Among participants without coprescription of aspirin, the risk of CVD was lower in naproxen initiators (10.3/1000 person-years) than in other NSAIDs initiators (13.2/1000 person-years; hazard ratio = 0.71, 95% confidence interval: 0.60, 0.85). Among participants with coprescription of aspirin, however, the risk of CVD was higher among naproxen initiators (36.9/1000 person-years) than that among other NSAIDs initiators (34.8/1000 person-years; hazard ratio = 1.48, 95% confidence interval: 1.12, 1.84). The association was significantly modified by coprescription of aspirin (P < 0.001). Similar findings were observed in the association of initiation of ibuprofen vs. other NSAIDs with the risk of CVD, which was significantly modified by coprescription of aspirin (P < 0.001). These findings suggest that osteoarthritis patients and clinicians should be aware of the potential CVD risk of concurrently taking naproxen or ibuprofen and low-dose aspirin., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

No current pharmacological approach is capable of simultaneously inhibiting the symptomatology and structural progression of osteoarthritis. M1 macrophages and activated synovial fibroblasts (SFs) mutually contribute to the propagation of joint pain and cartilage destruction in osteoarthritis. Here, we report the engineering of an apoptotic neutrophil membrane-camouflaged liposome (termed "NM@Lip") for precise delivery of triamcinolone acetonide (TA) by dually targeting M1 macrophages and activated SFs in osteoarthritic joints. NM@Lip has a high cellular uptake in M1 macrophages and activated SFs. Furthermore, TA-loaded NM@Lip (TA-NM@Lip) effectively repolarizes M1 macrophages to the M2 phenotype and transforms pathological SFs to the deactivated phenotype by inhibiting the PI3K/Akt pathway. NM@Lip retains in the joint for up to 28 days and selectively distributes into M1 macrophages and activated SFs in synovium with low distribution in cartilage. TA-NM@Lip decreases the levels of pro-inflammatory cytokines, chemokines, and cartilage-degrading enzymes in osteoarthritic joints. In a rodent model of osteoarthritis-related pain, a single intra-articular TA-NM@Lip injection attenuates synovitis effectively and achieves complete pain relief with long-lasting effects. In a rodent model of osteoarthritis-related joint degeneration, repeated intra-articular TA-NM@Lip injections induce no obvious cartilage damage and effectively attenuate cartilage degeneration. Taken together, TA-NM@Lip represents a promising nanotherapeutic approach for osteoarthritis therapy.

Competing Interests: Conflict of interest The authors declare that they have no conflict of interest.

Objective: Although most frequently used in experimental osteoarthritis (OA) pain induction, intra-articular mono-iodoacetate (MIA) injection lacks concluded references for dose selection and timing of intervention. Herein, we aimed to compare the pain intensity of rats induced by different doses of MIA and explored the trajectory of pain., Design: PubMed, Embase, and Web of Science were searched up to June 2021 for literatures involving MIA experiments investigating OA pain. Pain intensity was measured based on weightbearing distribution (WBD) and paw withdrawal thresholds (PWT), and the pain trajectory was constructed by evaluating pain intensity at a series of time points after MIA injection. A conventional meta-analysis was conducted., Results: A total of 140 studies were included. Compared with saline, MIA injections caused significantly higher pain intensity for WBD and PWT. Dose-response relationships between different doses of MIA and pain intensity were observed ( P -for-trend<0.05). A pronounced increase in pain occurred from day 0 to day 7, but the uptrend ceased between day 7 and day 14, after which the pain intensity continued to rise and reached the maximum by day 28., Conclusions: Pain intensity after intra-articular MIA injection increased in a dose-dependent manner and the pain trajectory manifested a specific pattern consistent with the pathological mechanisms of MIA-induced pain, providing possible clues for proper dose selection and timing of specific OA pain interventions.

In osteoarthritis (OA), chondrocytes undergo many pathological alternations that are linked with cellular senescence. However, the exact pathways that lead to the generation of a senescence-like phenotype in OA chondrocytes are not clear. Previously, we found that loss of estrogen receptor-α (ERα) was associated with an increased senescence level in human chondrocytes. Since DNA damage is a common cause of cellular senescence, we aimed to study the relationship among ERα levels, DNA damage, and senescence in chondrocytes. We first examined the levels of ERα, representative markers of DNA damage and senescence in normal and OA cartilage harvested from male and female human donors, as well as from male mice. The influence of DNA damage on ERα levels was studied by treating human chondrocytes with doxorubicin (DOX), which is an often-used DNA-damaging agent. Next, we tested the potential of overexpressing ERα in reducing DNA damage and senescence levels. Lastly, we explored the interaction between ERα and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Results indicated that the OA chondrocytes contained DNA damage and displayed senescence features, which were accompanied by significantly reduced ERα levels. Overexpression of ERα reduced the levels of DNA damage and senescence in DOX-treated normal chondrocytes and OA chondrocytes. Moreover, DOX-induced the activation of NF-κB pathway, which was partially reversed by overexpressing ERα. Taken together, our results demonstrated the critical role of ERα in maintaining the health of chondrocytes by inhibiting DNA damage and senescence. This study also suggests that maintaining the ERα level may represent a new avenue to prevent and treat OA., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background: Dietary magnesium deficiency, which is common in modern diet, has been associated with osteoarthritis (OA) susceptibility. Despite this clinical association, no study has addressed if dietary magnesium deficiency accelerates OA development, especially at molecular level. This study aimed to explore aggravating effects of dietary magnesium deficiency on cartilage damage in an injury-induced murine OA model and to determine the underlying mechanism., Methods: Twelve-week-old C57BL/6J mice subject to injury-induced OA modeling were randomized into different diet groups in which the mice were fed a diet with daily recommended magnesium content (500 mg/kg) or diets with low magnesium content (100 or 300 mg/kg). Articular cartilage damage was evaluated using the OARSI score. To determine molecular mechanisms in vitro, mouse chondrocytes were treated with media of low magnesium conditions at 0.1 and 0.4 mM, compared with normal magnesium condition at 0.7 mM as control. Anabolic and catabolic factors, autophagy markers, β-catenin, Wnt ligands, and a magnesium channel transient receptor potential cation channel subfamily member 7 (TRPM7) were analyzed by quantitative real-time PCR and immunoblotting. Autolysosomes were detected by DALGreen staining via fluorescence microscopy and autophagosomes were evaluated by transmission electron microscopy. Autophagy markers, β-catenin, and TRPM7 were assessed in vivo in the mouse cartilage, comparing between dietary magnesium deficiency and normal diet, by immunohistochemistry., Results: Dietary magnesium deficiency aggravated injury-induced cartilage damage, indicated by significant higher OARSI scores. Autophagy markers LC3-II and Beclin-1 were decreased both in low magnesium diet-fed mice and low magnesium-treated chondrocytes. The number of autolysosomes and autophagosomes was also reduced under low magnesium conditions. Moreover, magnesium deficiency induced decreased anabolic and increased catabolic effect of chondrocytes which could be restored by autophagy activator rapamycin. In addition, reduced autophagy under low magnesium conditions is mediated by activated Wnt/β-catenin signaling. The expression of TRPM7 also decreased in low magnesium diet-fed mice, indicating that downstream changes could be regulated through this channel., Conclusions: Dietary magnesium deficiency contributes to OA development, which is mediated by reduced autophagy through Wnt/β-catenin signaling activation. These findings indicated potential benefits of adequate dietary magnesium for OA patients or those individuals at high risk of OA., (© 2022. The Author(s).)

Objective: Patients with rheumatoid arthritis (RA) are at an increased risk of acquiring infections owing to immunologic dysfunction and use of potent immunomodulatory medications; however, few data are available on their risk of COVID-19. We estimated the rate of COVID-19 among RA participants and compared it with that of the general population., Methods: Using the Health Improvement Network, we identified RA patients before February 2020 and followed them to September 2020. We calculated the rate of COVID-19 among participants with RA and compared it with that of the general population using a Cox proportional hazards model, adjusting for potential confounders using overlap weighting of exposure score. We repeated the same analysis among participants with osteoarthritis, a nonautoimmune rheumatic disease, as a negative control exposure., Results: We identified 225 cases of suspected and confirmed COVID-19 among 17,268 RA patients, and 14,234 cases among 1,616,600 participants in the general population (1.4 versus 0.9/1,000 person-months), with the adjusted hazard ratio (HR adj ) being 1.19 (95% confidence interval [95% CI] 1.04-1.36). Confirmed COVID-19 cases developed in 46 RA participants and in 2,249 in the general population (0.3 versus 0.1/1,000 person-months), with the HR adj being 1.42 (95% CI 1.01-1.95). No statistically significant difference was observed for suspected and confirmed (HR 1.00 [95% CI 0.93-1.07]) or confirmed (HR 1.08 [95% CI 0.92-1.27]) COVID-19 rates between participants with osteoarthritis and the general population., Conclusion: RA, but not osteoarthritis, was associated with an increased risk of COVID-19. Our findings provide timely evidence to support recommendations that booster vaccines and priority access to anti-SARS-CoV-2 monoclonal antibody treatments should be encouraged for RA patients., (© 2021 American College of Rheumatology.)

Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis (OA). In this study, we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs (DMOADs). Specifically, human bone marrow-derived mesenchymal stromal cells (MSCs) were expanded in vitro up to passage 10 (P10-MSCs). Following their senescent phenotype formation, P10-MSCs were subjected to pellet culture in chondrogenic medium. Results from qRT-PCR, histology, and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents, when compared to that from normal passage 4 (P4)-MSCs. Interestingly, the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples, as demonstrated by RNA Sequencing data and other analysis methods. Lastly, the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics. The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage. The P4- and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans., (© 2022. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Systemic inflammatory factors have been implicated in symptomatic hand osteoarthritis (OA). Gut microbiome dysbiosis promotes systemic inflammation. The aim of this study was to examine the association between the gut microbiome and the presence of symptomatic hand OA in a population-based study., Methods: Study participants were subjects of the Xiangya Osteoarthritis Study, a community-based observational study conducted in the Hunan Province of China. Symptomatic hand OA was defined as the presence of both symptoms and radiographic OA in the same hand. The gut microbiome was analyzed using 16S ribosomal RNA gene sequencing in stool samples. We examined the relation of α-diversity, β-diversity, relative abundance of taxa, and potential bacterial functional pathways to symptomatic hand OA., Results: A total of 1,388 participants (mean age 61.3 years, 57.4% women) were included in the study, of whom 72 had symptomatic hand OA (prevalence of symptomatic hand OA 5.2%). Beta-diversity of the gut microbiome, but not α-diversity, was significantly associated with the presence of symptomatic hand OA (P = 0.003). Higher relative abundance of the genera Bilophila and Desulfovibrio as well as lower relative abundance of the genus Roseburia was associated with symptomatic hand OA. Most functional pathways (i.e., those annotated in the KEGG Ortholog hierarchy) that were observed to be altered in participants with symptomatic hand OA belonged to the amino acid, carbohydrate, and lipid metabolic pathways., Conclusion: This large, population-based study provides the first evidence that alterations in the composition of the gut microbiome were observed among study participants who had symptomatic hand OA, and a low relative abundance of Roseburia but high relative abundance of Bilophila and Desulfovibrio at the genus level were associated with prevalent symptomatic hand OA. These findings may help investigators understand the role of the microbiome in the development of symptomatic hand OA and could contribute to potential translational opportunities., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Introduction: Symptomatic treatments for osteoarthritis (OA) provide only small-to-moderate efficacy over placebo in randomised controlled trials (RCTs). Treatment guidelines therefore have emphasised the need to identify predictors of treatment response through subgroup and multiple regression analysis. Individual participant data (IPD) meta-analysis is recommended as an efficient approach for this purpose. To our knowledge, this has not been undertaken for oral non-steroidal anti-inflammatory drugs (NSAIDs), including paracetamol, in OA. In this IPD meta-analysis, we aim to identify RCTs with specific mechanistic features related to OA pain, such as joint inflammation. We hypothesise that NSAIDs may work better for participants with joint inflammation, whereas paracetamol may not., Methods and Analysis: A comprehensive literature search will be conducted on the databases of Web of Science, Embase, Medline, CINAHL, AMED and the Cochrane Library from 1 January 1998 to 1 December 2020. All RCTs related to oral NSAIDs or paracetamol including placebo-controlled trials in people with OA that have evaluated pain-related peripheral risk factors (eg, clinically detected knee effusion, synovial hypertrophy or effusion on imaging, knee morning stiffness, elevated serum C-reactive protein (CRP) level) and/or central pain risk factors (eg, pain elsewhere, depression, anxiety, sleep disturbance) will be retrieved. The outcome will be change in pain from baseline. Change in function and patient global assessment will also be included as outcomes if available. Investigators of all eligible trials will be contacted for IPD. Multilevel regression models will be used to identify predictors for the specific (active-placebo) and the overall treatment effect (change from baseline in active group)., Ethics and Dissemination: No identifiable data will be included in this study and no formal ethics approval is required as no new data collection will be processed. Results of this hypothesis-driven IPD meta-analysis will be disseminated through conference presentations and publication in peer-reviewed journals., Prospero Registration Number: CRD42020165098., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Osteoarthritis (OA) is the most prevalent form of arthritis and the major cause of disability and overall diminution of quality of life in the elderly population. Currently there is no cure for OA, partly due to the large gaps in our understanding of its underlying molecular and cellular mechanisms. Macrophage migration inhibitory factor (MIF) is a procytokine that mediates pleiotropic inflammatory effects in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, data on the role of MIF in OA is limited with conflicting results. We undertook this study to investigate the role of MIF in OA by examining MIF genotype, mRNA expression, and protein levels in the Newfoundland Osteoarthritis Study., Methods: One hundred nineteen end-stage knee/hip OA patients, 16 RA patients, and 113 healthy controls were included in the study. Two polymorphisms in the MIF gene, rs755622, and -794 CATT 5-8 , were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR followed by automated capillary electrophoresis, respectively. MIF mRNA levels in articular cartilage and subchondral bone were measured by quantitative polymerase chain reaction. Plasma concentrations of MIF, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) were measured by enzyme-linked immunosorbent assay., Results: rs755622 and -794 CATT 5-8 genotypes were not associated with MIF mRNA or protein levels or OA (all p ≥ 0.19). MIF mRNA level in cartilage was lower in OA patients than in controls (p = 0.028) and RA patients (p = 0.004), while the levels in bone were comparable between OA patients and controls (p = 0.165). MIF protein level in plasma was lower in OA patients than in controls (p = 3.01 × 10 -10 ), while the levels of TNF-α, IL-6 and IL-1β in plasma were all significantly higher in OA patients than in controls (all p ≤ 0.0007). Multivariable logistic regression showed lower MIF and higher IL-1β protein levels in plasma were independently associated with OA (OR per SD increase = 0.10 and 8.08; 95% CI = 0.04-0.19 and 4.42-16.82, respectively), but TNF-α and IL-6 became non-significant., Conclusions: Reduced MIF mRNA and protein expression in OA patients suggested MIF might have a protective role in OA and could serve as a biomarker to differentiate OA from other joint disorders.

Endoplasmic reticulum (ER) stress has been shown to promote chondrocyte apoptosis and osteoarthritis (OA) progression, but the precise mechanisms via which ER stress is modulated in OA remain unclear. Here we report that DEP domain-containing mTOR-interacting protein (DEPTOR) negatively regulated ER stress and OA development independent of mTOR signaling. DEPTOR is ubiquitinated in articular chondrocytes and its expression is markedly reduced along with OA progression. Deletion of DEPTOR in chondrocytes significantly promoted destabilized medial meniscus (DMM) surgery-induced OA development, whereas intra-articular injection of lentivirus-expressing DEPTOR delayed OA progression in mice. Proteomics analysis revealed that DEPTOR interplayed with TRC8, which promoted TRC8 auto-ubiquitination and degraded by the ubiquitin-proteasome system (UPS) in chondrocytes. Loss of DEPTOR led to TRC8 accumulation and excessive ER stress, with subsequent chondrocyte apoptosis and OA progression. Importantly, an inhibitor of ER stress eliminated chondrocyte DEPTOR deletion-exacerbated OA in mice. Together, these findings establish a novel mechanism essential for OA pathogenesis, where decreasing DEPTOR in chondrocytes during OA progression relieves the auto-ubiquitination of TRC8, resulting in TRC8 accumulation, excessive ER stress, and OA progression. Targeting this pathway has promising therapeutic potential for OA treatment. © 2020 American Society for Bone and Mineral Research (ASBMR)., (© 2020 American Society for Bone and Mineral Research (ASBMR).)

Objectives: To examine trends in the initial prescription of commonly-prescribed analgesics and patient- as well as practice-level factors related to their selection in incident OA., Methods: Patients consulting with incident clinical OA between 2000-2016 were identified within The Health Improvement Network in the United Kingdom (UK) general practice. Excluded were patients who had history of cancer or were prescribed the analgesics of interest within 6 months before diagnosis of OA. Initial analgesic prescription included oral non-selective NSAID, oral selective cyclooxygenase-2 inhibitor, topical NSAID, paracetamol, topical salicylate or oral/transdermal opioid within 1 month after OA diagnosis., Results: ∼44% of patients with incident OA (n = 125 696) were prescribed one of these analgesics. Incidence of oral NSAID prescriptions decreased whereas other analgesic prescriptions, including oral opioid prescriptions, increased (all P-for-trend < 0.001). Patients with a history of gastrointestinal disease were more likely to receive topical NSAIDs, paracetamol or oral/transdermal opioids. Only 38% of patients with history of gastrointestinal disease and 21% of patients without it had co-prescription of gastroprotective agent with oral NSAIDs. Oral/transdermal opioid prescription was higher among the elderly (≥65 years), women, obesity, current smoker, and patients with gastrointestinal, cardiovascular or chronic kidney disease. Prescription of oral opioids increased with social deprivation (P-for-trend < 0.05) and was highest in Scotland, whereas transdermal opioid prescription was highest in Northern Ireland (all P-for-homogeneity-test < 0.05)., Conclusion: The initial prescription pattern of analgesics for OA has changed over time in the UK. Co-prescription of gastroprotective agents with oral NSAIDs remains suboptimal, even among those with prior gastrointestinal disease., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Osteoarthritis is a leading cause of immobility and joint replacement, two strong risk factors for venous thromboembolism (VTE). We aimed to examine the relation of knee, hip and hand osteoarthritis to the risk of VTE and investigate joint replacement as a potential mediator., Methods: We conducted three cohort studies using data from The Health Improvement Network. Up to five individuals without osteoarthritis were matched to each case of incident knee (n=20 696), hip (n=10 411) or hand (n=6329) osteoarthritis by age, sex, entry time and body mass index. We examined the relation of osteoarthritis to VTE (pulmonary embolism and deep vein thrombosis) using a multivariable Cox proportional hazard model., Results: VTE developed in 327 individuals with knee osteoarthritis and 951 individuals without osteoarthritis (2.7 vs 2.0 per 1000 person-years), with multivariable-adjusted HR being 1.38 (95% CI 1.23 to 1.56). The indirect effect (HR) of knee osteoarthritis on VTE through knee replacement was 1.07 (95% CI 1.01 to 1.15), explaining 24.8% of its total effect on VTE. Risk of VTE was higher in hip osteoarthritis than non-osteoarthritis (3.3 vs 1.8 per 1000 person-years; multivariable-adjusted HR=1.83, 95% CI 1.56 to 2.13). The indirect effect through hip replacement yielded an HR of 1.14 (95% CI 1.04 to 1.25), explaining 28.1% of the total effect. No statistically significant difference in VTE risk was observed between hand osteoarthritis and non-osteoarthritis (1.5 vs 1.6 per 1000 person-years; multivariable-adjusted HR=0.88, 95% CI 0.67 to 1.16)., Conclusion: Our large population-based cohort study provides the first evidence that knee or hip osteoarthritis, but not hand osteoarthritis, was associated with an increased risk of VTE, and such an association was partially mediated through knee or hip replacement., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study investigated articular cartilage (AC) homeostasis and different signaling pathways involved in the superior cartilage regeneration of Murphy Roths large (MRL/MpJ) mice previously reported. We collected uninjured and destabilized medial meniscus (DMM)-injured knees from 8-wk-old C57BL/6J and MRL/MpJ mice. We used micro-computed tomography (microCT), histology, and immunohistochemistry to evaluate AC homeostasis and repair. We used the ear punch model to investigate the role of angiogenesis and inflammation in the superior healing of MRL/MpJ mice. We found fewer β-catenin and more pSMAD5 positive cells in the uninjured AC of MRL/MpJ mice than that from C57BL/6J mice. MRL/MpJ mice exhibited better AC repair in DMM-induced OA, as indicated by microCT results, Alcian blue, and Safranin O staining. Mechanistically, fewer β-catenin, pSMAD2-, pSMAD3-, a disintegrin and metalloproteinase with thrombospondin motifs 4-, matrix metalloproteinase (MMP) 9-, and MMP13-positive cells and more proliferating cell nuclear antigen- and pSMAD5-positive cells were found in the DMM-injured AC in MRL/MpJ mice than in normal mice. The accelerated ear wound healing of MRL/MpJ mice correlated with enhanced angiogenesis and macrophage polarization toward the M2a phenotype through elevated IL-10 and IL-4 expressing cells. Collectively, our study revealed that down-regulation of pSMAD2/3, β-catenin, and MMPs and up-regulation of pSMAD5 and M2a macrophage polarization contribute to the enhanced cartilage repair observed in MRL/MpJ mice.-Deng, Z., Gao, X., Sun, X., Amra, S., Lu, A., Cui, Y., Eltzschig, H. K., Lei, G., Huard, J. Characterization of articular cartilage homeostasis and the mechanism of superior cartilage regeneration of MRL/MpJ mice.

Importance: An American Academy of Orthopaedic Surgeons guideline recommends tramadol for patients with knee osteoarthritis, and an American College of Rheumatology guideline conditionally recommends tramadol as first-line therapy for patients with knee osteoarthritis, along with nonsteroidal anti-inflammatory drugs., Objective: To examine the association of tramadol prescription with all-cause mortality among patients with osteoarthritis., Design, Setting, and Participants: Sequential, propensity score-matched cohort study at a general practice in the United Kingdom. Individuals aged at least 50 years with a diagnosis of osteoarthritis in the Health Improvement Network database from January 2000 to December 2015, with follow-up to December 2016., Exposures: Initial prescription of tramadol (n = 44 451), naproxen (n = 12 397), diclofenac (n = 6512), celecoxib (n = 5674), etoricoxib (n = 2946), or codeine (n = 16 922)., Main Outcomes and Measures: All-cause mortality within 1 year after initial tramadol prescription, compared with 5 other pain relief medications., Results: After propensity score matching, 88 902 patients were included (mean [SD] age, 70.1 [9.5] years; 61.2% were women). During the 1-year follow-up, 278 deaths (23.5/1000 person-years) occurred in the tramadol cohort and 164 (13.8/1000 person-years) occurred in the naproxen cohort (rate difference, 9.7 deaths/1000 person-years [95% CI, 6.3-13.2]; hazard ratio [HR], 1.71 [95% CI, 1.41-2.07]), and mortality was higher for tramadol compared with diclofenac (36.2/1000 vs 19.2/1000 person-years; HR, 1.88 [95% CI, 1.51-2.35]). Tramadol was also associated with a higher all-cause mortality rate compared with celecoxib (31.2/1000 vs 18.4/1000 person-years; HR, 1.70 [95% CI, 1.33-2.17]) and etoricoxib (25.7/1000 vs 12.8/1000 person-years; HR, 2.04 [95% CI, 1.37-3.03]). No statistically significant difference in all-cause mortality was observed between tramadol and codeine (32.2/1000 vs 34.6/1000 person-years; HR, 0.94 [95% CI, 0.83-1.05])., Conclusions and Relevance: Among patients aged 50 years and older with osteoarthritis, initial prescription of tramadol was associated with a significantly higher rate of mortality over 1 year of follow-up compared with commonly prescribed nonsteroidal anti-inflammatory drugs, but not compared with codeine. However, these findings may be susceptible to confounding by indication, and further research is needed to determine if this association is causal.

Objective: To investigate the efficacy and safety of the pulsed electromagnetic field (PEMF) therapy in treating osteoarthritis (OA)., Design: Meta-analysis., Data Sources: PubMed, Embase, the Cochrane Library and Web of Science were searched through 13 October 2017., Eligibility Criteria for Selecting Studies: Randomised controlled trials compared the efficacy of PEMF therapy with sham control in patients with OA., Data Extraction and Synthesis: Pain, function, adverse effects and characteristics of participants were extracted. RevMan V.5.2 was used to perform statistical analyses., Results: Twelve trials were included, among which ten trials involved knee OA, two involved cervical OA and one involved hand OA. The PEMF group showed more significant pain alleviation than the sham group in knee OA (standardised mean differences (SMD)=-0.54, 95% CI -1.04 to -0.04, p=0.03) and hand OA (SMD=-2.85, 95% CI -3.65 to -2.04, p<0.00001), but not in cervical OA. Similarly, comparing with the sham-control treatment, significant function improvement was observed in the PEMF group in both knee and hand OA patients (SMD=-0.34, 95% CI -0.53 to -0.14, p=0.0006, and SMD=-1.49, 95% CI -2.12 to -0.86, p<0.00001, respectively), but not in patients with cervical OA. Sensitivity analyses suggested that the exposure duration <=30 min per session exhibited better effects compared with the exposure duration >30 min per session. Three trials reported adverse events, and the combined results showed that there was no significant difference between PEMF and the sham group., Conclusions: PEMF could alleviate pain and improve physical function for patients with knee and hand OA, but not for patients with cervical OA. Meanwhile, a short PEMF treatment duration (within 30 min) may achieve more favourable efficacy. However, given the limited number of study available in hand and cervical OA, the implication of this conclusion should be cautious for hand and cervical OA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To compare the efficacy and safety of topical non-steroidal anti-inflammatory drugs (NSAIDs), including salicylate, for the treatment of osteoarthritis (OA)., Methods: PubMed, Embase, Cochrane Library and Web of Science were searched from 1966 to January 2017. Randomised controlled trials (RCTs) comparing topical NSAIDs with placebo or each other in patients with OA and observational studies comparing topical NSAIDs with no treatment or each other irrespective of disease were included. Two investigators identified studies and independently extracted data. Bayesian network and conventional meta-analyses were conducted. The primary outcomes were pain relief for RCTs and risk of adverse effects (AEs) for observational studies., Results: 43 studies, comprising 36 RCTs (7 900 patients with OA) and seven observational studies (218 074 participants), were included. Overall, topical NSAIDs were superior to placebo for relieving pain (standardised mean difference (SMD)=-0.30, 95% CI -0.40 to -0.20) and improving function (SMD=-0.35, 95% CI -0.45 to -0.24) in OA. Of all topical NSAIDs, diclofenac patches were most effective for OA pain (SMD=-0.81, 95% CI -1.12 to -0.52) and piroxicam was most effective for functional improvement (SMD=-1.04, 95% CI -1.60 to -0.48) compared with placebo. Although salicylate gel was associated with higher withdrawal rates due to AEs, the remaining topical NSAIDs were not associated with any increased local or systemic AEs., Conclusions: Topical NSAIDs were effective and safe for OA. Diclofenac patches may be the most effective topical NSAID for pain relief. No serious gastrointestinal and renal AEs were observed in trials or the general population. However, confirmation of the cardiovascular safety of topical NSAIDs still warrants further observational study., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The aim of this study was to determine the specific microRNA (miRNA) that regulates expression of osteopontin (OPN) in osteoarthritis (OA). The potential regulatory miRNAs for OPN messenger RNA (mRNA) were predicted by miRNA prediction programs. Among eight potential regulatory miRNAs, miR-220b, miR-513a-3p and miR-548n increased, while miR-181a, miR-181b, miR-181c, miR-181d and miR-127-5p decreased in OA patients. miRNA-127-5p mimics suppressed OPN production as well as the activity of a reporter construct containing the 3'-UTR of human OPN mRNA. In addition, mutation of miR-127-5p binding site in the 3'-UTR of OPN mRNA abolished miR-127-5p-mediated repression of reporter activity. Conversely, treatment with miR-127-5p inhibitor increased reporter activity and OPN production. Interestingly, miR-127-5p inhibited proliferation of chondrocytes through OPN. In conclusion, miRNA-127-5p is an important regulator of OPN in human chondrocytes and may contribute to the development of OA.

Osteoarthritis (OA) is a common form of arthritis in humans. It has long been regarded as a non-inflammatory disease, but a degree of inflammation is now recognized as being a vital inducer of subpopulation of OA. Besides inflammation, the establishment and development of OA are associated with alterations in metabolism and profiles of amino acids (AA), including glutamate- and arginine-family AA as well as their related metabolites (e.g., creatinine, hydroxyproline, γ-aminobutyrate, dimethylarginines and homoarginine). Functional AA (e.g., glutamine, arginine, glutamate, glycine, proline, and tryptophan) have various benefits (i.e., anti-inflammation and anti-oxidation) in treatment of inflammation-associated diseases, including OA. Thus, these AA have potential as immunomodulatory nutrients for patients with inflammation-induced OA.

Intestinal microbiota is highly involved in host physiology and pathology through activity of the microbiome and its metabolic products. Osteoarthritis (OA) is a common form of arthritis characterized by articular cartilage destruction and osteophyte formation. Although various person-level risk factors, such as age, sex, and obesity, have been proposed for the pathogenesis of OA, the underlying links between these person-level factors and OA are still enigmatic. Based on the current understanding in the crosstalk between intestinal microbiota and these risk factors, intestinal microbiota could be considered as a major hidden risk factor that provides a unifying mechanism to explain the involvement of these person-level risk factors in OA.

Objective: To investigate the surgical techniques and clinical outcomes of total hip replacement for patients with end-stage osteoarthritis secondary to developmental dysplasia of the hip., Methods: From May 2004 to March 2008, a total of 36 total hip replacements were performed in 32 patients with end-stage osteoarthritis secondary to developmental dysplasia of the hip. The acetabulum cup was reconstructed in the corresponding anatomical position in all cases. Cemented components were used in 16 hips, and cementless components in the other 20 hips. The mean follow-up was 31.3 months. Clinical outcomes were determined with Harris hip score. Radiographs were taken after the surgery and in every follow-up examination for further reference., Results: All patients postoperatively gained a limb lengthening with an average of (3.4+/-1.3) cm. Three patients had complications, 2 had nondisplaced fractures of the proximal part of the femur,and 1 sciatic nerve palsy which disappeared after 3 months. There was no infection, dislocation and symptomatic deep vein thrombosis. Compared with preoperation, the mean Harris hip scores on the 3rd day, the 14th day after the operation and at the last follow-up were all improved significantly (all P<0.05). There was no loosening, migration, heterotopic ossification radiographically, and no revision during the follow-up., Conclusion: Total hip replacement is an effective treatment for patients with end-stage osteoarthritis secondary to developmental dysplasia of the hip. The key is to place the acetabulum cup in the corresponding anatomical position, and choose proper prosthesises during the surgery.

ObjectiveThe current guidelines recommend weight loss for patients with overweight or obesity and knee or hip osteoarthritis (OA); however, there is a paucity of data on the relation of weight loss to death among patients with OA. We aimed to examine the relation of the rate of weight loss induced by antiobesity medications over one year to all-cause mortality among patients with overweight or obesity and knee or hip OA.MethodsUsing the IQVIA Medical Research Database, we identified people with overweight or obesity and knee or hip OA. We emulated analyses of a hypothetical target trial to assess the effect of slow-to-moderate (2%-10%) or fast (≥10%) weight loss induced by the initiation of antiobesity medications within one year on all-cause mortality and secondary outcomes over five years' follow-up.ResultsAmong 6,524 participants, the five-year all-cause mortality rates were 5.3%, 4.0%, and 5.4% for weight gain or stable, slow-to-moderate weight loss, and fast weight loss arms, respectively. Compared with the weight gain or stable arm, hazard ratios of all-cause mortality were 0.72 (95% confidence interval [CI] 0.56-0.92) for the slow-to-moderate weight loss arm and 0.99 (95% CI 0.67-1.44) for the fast weight loss arm. We found dose-response protective effects of weight loss on incident hypertension, type 2 diabetes, and venous thromboembolism but a slightly higher risk of cardiovascular disease, albeit not statistically significant, in the fast rate of weight loss arm than in the weight gain or stable arm and no significant relations of weight loss to the risk of cancer.ConclusionIn this population-based study, a slow-to-moderate, but not fast, rate of weight loss induced by antiobesity medications is associated with a lower risk of all-cause mortality in people with overweight or obesity and knee or hip OA.

Nonsteroidal antiinf lammatory drugs (NSAIDs) remain the mainstay of the pharmacologic management for relieving osteoarthritis pain, and low-dose aspirin is often prescribed to osteoarthritis patients who are at high risk of cardiovascular disease (CVD). We conducted cohort studies using data from The Health Improvement Network (THIN) database (2000-2019) to assess whether the relationship of initiation of naproxen or ibuprofen vs. initiation of other NSAIDs (excluding both naproxen and ibuprofen), respectively, to the risk of CVD was modified by coprescription of low-dose aspirin among the participants with osteoarthritis. Among participants without coprescription of aspirin, the risk of CVD was lower in naproxen initiators (10.3/1000 person-years) than in other NSAIDs initiators (13.2/1000 person-years; hazard ratio = 0.71, 95% confidence interval: 0.60, 0.85). Among participants with coprescription of aspirin, however, the risk of CVD was higher among naproxen initiators (36.9/1000 person-years) than that among other NSAIDs initiators (34.8/1000 person-years; hazard ratio = 1.48, 95% confidence interval: 1.12, 1.84). The association was significantly modified by coprescription of aspirin (P < 0.001). Similar findings were observed in the association of initiation of ibuprofen vs. other NSAIDs with the risk of CVD, which was significantly modified by coprescription of aspirin (P < 0.001). These findings suggest that osteoarthritis patients and clinicians should be aware of the potential CVD risk of concurrently taking naproxen or ibuprofen and low-dose aspirin.

OBJECTIVE: To assess the relation of symptomatic knee osteoarthritis (OA), knee pain, and radiographic knee OA to All-cause mortality and to identify mediators in the causal pathway. METHODS: Participants from the Osteoarthritis Initiative were divided into 4 groups: 1) symptomatic knee OA (i.e., both radiographic knee OA [Kellgren/Lawrence grade ≥2] and knee pain); 2) knee pain only; 3) radiographic knee OA only; and 4) neither radiographic knee OA nor knee pain. We examined the relation of knee OA status to All-cause mortality using a multivariable Cox proportional hazards model and assessed the extent to which the association was mediated by disability, physical component summary (PCS) and mental component summary (MCS) scores for quality of life (QoL), and use of oral pain-relief medications (i.e., nonsteroidal antiinflammatory drugs and opioids). RESULTS: Among 4,796 participants, 282 died over the 96-month follow-up period. Compared with those with neither radiographic knee OA nor knee pain, multivariable-adjusted hazard ratios (HRs) of mortality were 2.2 (95% confidence interval [95% CI] 1.6-3.1) for symptomatic knee OA, 0.9 (95% CI 0.6-1.4) for knee pain only, and 2.0 (95% CI 1.4-2.9) for radiographic knee OA only, respectively. Indirect effects (HRs) of symptomatic knee OA on mortality via disability and PCS of QoL were 1.1 (95% CI 1.0-1.4) and 1.2 (95% CI 1.0-1.4), respectively. No apparent mediation effect was observed through either MCS of QoL or oral pain-relief medications use. CONCLUSION: Participants with either symptomatic or radiographic knee OA were at an increased risk of All-cause mortality. Increased risk of mortality from symptomatic knee OA was partially mediated through its effect on disability and PCS of QoL.

To investigate to what extent the higher risk of tibiofemoral radiographic osteoarthritis (TFROA) in females vs. males can be explained by knee malalignment. Using data from Multicenter Osteoarthritis Study (MOST) and Osteoarthritis Initiative (OAI), we examined the relation of sex to the incident medial and lateral TFROA and performed mediation analyses to assess to what extent varus and valgus malalignments account for sex differences in the incident medial or lateral TFROA. Of the 3462 knees without medial and lateral TFROA in MOST, the 7-year risks of medial and lateral TFROA were 16.9% and 10.0% in females, and 15.8% and 4.2% in males, respectively. Females had 2.31-fold (95% confidence interval [95% CI]: 1.73 to 3.08) higher incident lateral TFROA than males, and the relative risk (RR) of the indirect effect of sex on lateral TFROA through valgus malalignment was 1.15 (95% CI: 1.09 to 1.20), accounting for 23% of its total effect on lateral TFROA. In OAI (n = 3095 knees), females had 1.54-fold (95% CI: 1.15 to 2.04) higher incident lateral TFROA than males, and RR of the indirect effect of sex on lateral TFROA through valgus malalignment was 1.10 (95% CI: 1.04 to 1.21), accounting for 26% of its total effect on lateral TFROA. No apparent sex difference in the incident medial TFROA was found in MOST (RR = 1.05, 95% CI: 0.89 to 1.25) or OAI (RR = 1.02, 95% CI: 0.84 to 1.19). Females had a higher risk of developing lateral TFROA than males; however, valgus malalignment only modestly explained such a difference. [ABSTRACT FROM AUTHOR]

Melatonin exhibits potential for pain relief and long‐term safety profile. We examined the analgesic effects of oral melatonin on osteoarthritis (OA) and investigated the underlying mechanism. Using data from a UK primary care database, we conducted a cohort study in individuals with OA to compare the number of oral analgesic prescriptions and the risk of knee/hip replacement between melatonin initiators and hypnotic benzodiazepines (i.e., active comparator) initiators using quantile regression models and Cox‐proportional hazard models, respectively. To elucidate causation, we examined the effects of melatonin on pain behaviors and explored several metabolites that may serve as potential regulatory agents of melatonin in the monoiodoacetate rat model of OA. Using data from another community‐based cohort study, that is, the Xiangya OA Study, we verified the association between the key serum metabolite and incident symptomatic knee OA. Compared with the hypnotic benzodiazepines cohort (n = 8135), the melatonin cohort (n = 813) had significantly fewer subsequent prescriptions of oral analgesics (50th percentile: 5 vs. 7, 75th percentile: 19 vs. 29, and 99th percentile: 140 vs. 162) and experienced a lower risk of knee/hip replacement (hazard ratio = 0.47, 95% Cl: 0.30–0.73) during the follow‐up period. In rats, oral melatonin alleviated pain behaviors and increased serum levels of glycine. There was an inverse association between baseline serum glycine levels and the risk of incident symptomatic knee OA in humans (n = 760). In conclusion, our findings indicate that oral melatonin shows significant potential to be a novel treatment for OA pain. The potential role of glycine in its analgesic mechanism warrants further investigation. [ABSTRACT FROM AUTHOR]

Objectives: There is still a large unmet need for novel osteoarthritis (OA) treatments that could provide clinically important effects on long-term pain relief (≥12 months). We examined the relation of bariatric surgery along with weight loss to analgesic prescription and all-cause mortality among individuals with OA.Methods: We conducted a cohort study among individuals with OA using The Health Improvement Network. We compared the rate of no analgesic prescription ≥12 consecutive months and the risk of all-cause mortality using inverse probability weighting Cox-proportional hazard models and the difference in number of analgesic prescriptions (non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in the 50th, 75th and 90th percentiles using quantile regression model between bariatric and non-bariatric cohorts.Results: Included were 588,494 individuals (694 had bariatric surgery). Compared with non-bariatric group, the rate of no analgesic prescription ≥12 consecutive months was higher (HR = 1.23, 95% CI: 1.08-1.38) in bariatric surgery group, and the number of analgesic prescriptions was lower in the 75th (44 vs 58) and 90th (74 vs 106) percentiles during a mean follow-up of 4.3 years. All-cause mortality in bariatric surgery group was lower than comparison group (HR = 0.46, 95% CI: 0.41-0.51).Conclusion: This study presents the first evidence that bariatric surgery was associated with decreased long-term analgesic prescription and decreased all-cause mortality among individuals with OA. However, our findings may be overestimated owing to intractable confounding by indication for bariatric surgery; thus, future studies (e.g., clinical trials) are warranted. [ABSTRACT FROM AUTHOR]

Objectives: Osteoarthritis is a leading cause of immobility and joint replacement, two strong risk factors for venous thromboembolism (VTE). We aimed to examine the relation of knee, hip and hand osteoarthritis to the risk of VTE and investigate joint replacement as a potential mediator.Methods: We conducted three cohort studies using data from The Health Improvement Network. Up to five individuals without osteoarthritis were matched to each case of incident knee (n=20 696), hip (n=10 411) or hand (n=6329) osteoarthritis by age, sex, entry time and body mass index. We examined the relation of osteoarthritis to VTE (pulmonary embolism and deep vein thrombosis) using a multivariable Cox proportional hazard model.Results: VTE developed in 327 individuals with knee osteoarthritis and 951 individuals without osteoarthritis (2.7 vs 2.0 per 1000 person-years), with multivariable-adjusted HR being 1.38 (95% CI 1.23 to 1.56). The indirect effect (HR) of knee osteoarthritis on VTE through knee replacement was 1.07 (95% CI 1.01 to 1.15), explaining 24.8% of its total effect on VTE. Risk of VTE was higher in hip osteoarthritis than non-osteoarthritis (3.3 vs 1.8 per 1000 person-years; multivariable-adjusted HR=1.83, 95% CI 1.56 to 2.13). The indirect effect through hip replacement yielded an HR of 1.14 (95% CI 1.04 to 1.25), explaining 28.1% of the total effect. No statistically significant difference in VTE risk was observed between hand osteoarthritis and non-osteoarthritis (1.5 vs 1.6 per 1000 person-years; multivariable-adjusted HR=0.88, 95% CI 0.67 to 1.16).Conclusion: Our large population-based cohort study provides the first evidence that knee or hip osteoarthritis, but not hand osteoarthritis, was associated with an increased risk of VTE, and such an association was partially mediated through knee or hip replacement. [ABSTRACT FROM AUTHOR]

Objective Statins are reported to have a potential benefit on progression of OA and on disease activity in RA, but existing evidence is conflicting. Our objective was to examine whether statins associate with reduction in the risk for joint replacement due to OA and RA. Methods This was a propensity score-matched cohort study. Electronic health records from the UK Clinical Practice Research Datalink were used. We selected people prescribed statins and people never prescribed statins. Each statin user was matched to a non-user by age, gender, practice and propensity score for statin prescription. The main outcome measures were knee or hip joint replacement overall, and specifically because of OA or RA. The association between statins and risk of joint replacement was assessed using Cox proportional hazard regression. Statin exposure was categorized according to the potency of reducing low-density lipoprotein as low (21–28%), medium (32–38%) or high (42–55%) intensity. Results A total of 178 467 statin users were matched with 178 467 non-users by age, gender, practice and propensity score. Overall, statin was not associated with reduced risk of knee or hip replacement (hazard ratio 0.99, 95% CI: 0.97, 1.03), unless prescribed at high strength (0.86, 0.75–0.98). The reduced risk was only observed for joint replacement due to RA (0.77, 0.63–0.94) but not OA (0.97, 0.94–1.01). Conclusion Statins at high intensity may reduce the risk of hip or knee replacement. This effect may be RA specific. Further studies to investigate mechanisms of risk reduction and the impact in people with RA are warranted. [ABSTRACT FROM AUTHOR]

Objectives: To examine the association between body composition and osteoarthritis (OA). Methods: An extensive literature review was performed to identify studies that examined the association between body composition and OA. The mean difference (MD), odds ratio (OR), relative risk (RR) and corresponding 95% confidence intervals (CIs) were determined using RevMan statistical software. Results: A total of 19 studies were included. The combined MD showed the fat mass of the subjects with knee OA was higher than that of the control group (MD 4.38, 95% CI: 2.84‐5.92). Both fat mass and fat mass percentage were positively associated with knee OA (ORs ranged from 1.49, 95% CI: 1.15‐1.92, to 2.37, 95% CI: 1.18‐4.74). Similar findings were observed in hip and hand joints as well (ORs ranged from 1.20, 95% CI: 1.08‐1.32, to 1.87, 95% CI: 1.11‐3.15), and such results were also confirmed by most cohort studies of knee and hip OA (RRs ranged from 0.98, 95% CI: 0.95‐1.01, to 3.60, 95% CI: 2.60‐5.00). Lean mass was also positively associated with knee OA (OR 1.48, 95% CI: 1.13‐1.94). However, lean mass percentage was negatively associated with knee OA (OR 0.65, 95% CI: 0.46‐0.92). Conclusions: Both fat mass and fat mass percentage were likely to be risk factors for knee, hip and hand OA. Similarly, lean mass also seemed to be a risk factor for knee OA, while lean mass percentage seemed to be a protective factor. [ABSTRACT FROM AUTHOR]

Aim: To systematically examine the existing literature on the associations between chondrocalcinosis (CC) and osteoarthritis (OA) at different joints, and to quantify such associations through meta‐analysis. Methods: PubMed, Embase and Scopus databases were searched through from inception to June 2017. Cohort, case‐control or cross‐sectional studies were included if they examined the association between CC and OA. Data on the odds ratios (OR) and their 95% confidence intervals (CI) of the prevalence or progression of OA between the CC group and non‐CC group with respect to the same joint were extracted. Results: A total of 14 studies were identified. Twelve studies were eligible for assessing the association between knee CC and knee OA. The combined data showed a positive association between them (OR = 2.84; 95% CI, 2.12‐3.81; P < 0.001). Three studies were eligible for assessing the association between hip CC and hip OA. The data on the OR could only be extracted from one study (OR = 0.92; 95% CI, 0.68‐1.24; P = 0.59). Two studies were eligible for assessing the association between hand CC and hand OA, and the data on the OR could only be extracted from one study which reported significant associations between CC and OA at the metacarpophalangeal joint (OR = 4.75; 95% CI, 2.12‐10.64; P < 0.001) and the wrist joint (OR = 4.44; 95% CI, 3.56‐5.54; P < 0.001). Conclusion: This study established a strong association between knee CC and knee OA. However, the associations between CC and OA at the hip or hand still remain controversial and warrant further study. [ABSTRACT FROM AUTHOR]

Objectives: To compare the efficacy and safety of topical non-steroidal anti-inflammatory drugs (NSAIDs), including salicylate, for the treatment of osteoarthritis (OA).Methods: PubMed, Embase, Cochrane Library and Web of Science were searched from 1966 to January 2017. Randomised controlled trials (RCTs) comparing topical NSAIDs with placebo or each other in patients with OA and observational studies comparing topical NSAIDs with no treatment or each other irrespective of disease were included. Two investigators identified studies and independently extracted data. Bayesian network and conventional meta-analyses were conducted. The primary outcomes were pain relief for RCTs and risk of adverse effects (AEs) for observational studies.Results: 43 studies, comprising 36 RCTs (7 900 patients with OA) and seven observational studies (218 074 participants), were included. Overall, topical NSAIDs were superior to placebo for relieving pain (standardised mean difference (SMD)=-0.30, 95% CI -0.40 to -0.20) and improving function (SMD=-0.35, 95% CI -0.45 to -0.24) in OA. Of all topical NSAIDs, diclofenac patches were most effective for OA pain (SMD=-0.81, 95% CI -1.12 to -0.52) and piroxicam was most effective for functional improvement (SMD=-1.04, 95% CI -1.60 to -0.48) compared with placebo. Although salicylate gel was associated with higher withdrawal rates due to AEs, the remaining topical NSAIDs were not associated with any increased local or systemic AEs.Conclusions: Topical NSAIDs were effective and safe for OA. Diclofenac patches may be the most effective topical NSAID for pain relief. No serious gastrointestinal and renal AEs were observed in trials or the general population. However, confirmation of the cardiovascular safety of topical NSAIDs still warrants further observational study. [ABSTRACT FROM AUTHOR]

Osteopontin (OPN) is associated with the severity and progression of osteoarthritis (OA); however, the mechanism of OPN in the pathogenesis of OA is unknown. In this study, we found that OA patients had higher abundance of OPN and matrix metalloproteinase 13 (MMP13). In chondrocytes, we showed that OPN promoted the production of MMP13 and activation of NF-κB pathway by increasing the abundance of p65 and phosphorylated p65 and translocation of p65 protein from cytoplasm to nucleus. Notably, inhibition of NF-κB pathway by inhibitor suppressed the production of MMP13 induced by OPN treatment. In conclusion, OPN induces production of MMP13 through activation of NF-κB pathway. [ABSTRACT FROM AUTHOR]

Objectives. This study is undertaken to investigate the relation between osteopontin (OPN) and Wnt5a expression in the progression and pathogenesis of osteoarthritis (OA). Methods. 50 cartilage tissues from knee OA patients and normal controls were divided into four groups of severe, moderate, minor, and normal lesions based on the modified grading system of Mankin. Immunohistochemistry and real-time PCR were utilized to analyze the OPN and Wnt5a expression in articular cartilage. Besides, the relations between OPN and Wnt5a expression and the severity of OA were explored. Results. OPN and Wnt5a could be identified in four groups’ tissues. Amongst the groups, the intercomparisons of OPN expression levels showed statistical differences (P<0.01). Besides, the intercomparisons of Wnt5a expression degrees showed statistical differences (P<0.05), except that between the minor and normal groups (P>0.05). The scores of Mankin were demonstrated to relate to OPN expression (r=-0.847, P<0.01) and Wnt5a expression in every group (r=-0.843, P<0.01). Also, a positive correlation can be observed between the OPN and Wnt5a expression (r=0.769, P<0.01). Conclusion. In articular cartilage, the expressions of OPN and Wnt5a are positively related to progressive damage of knee OA joint. The correlation between Wnt5a and OPN might be important to the progression and pathogenesis of knee OA. [ABSTRACT FROM AUTHOR]