Increased Risk Of Osteoarthritis Research Articles

Long- and Intermediate-Term Ambient Particulate Pollution Is Associated with Increased Osteoarthritis Risk: A Population-Based Prospective Analysis.

Recent studies found the intrusion and retention of exogenous fine particles into joints, but epidemiological data for long- and intermediate-term exposure associations are scare. Here, all urban working, retired employee, and rural residents (16.78 million) in Beijing from January 1, 2011 to December 31, 2019 were included to investigate the effects of long- and intermediate-term ambient particulate exposure on development of osteoarthritis. We identified 1,742,067 participants as first-visit patients with osteoarthritis. For each interquartile range increase in annual PM2.5 (23.32 μg/m3) and PM10 (23.92 μg/m3) exposure concentration, the pooled hazard ratios were respectively 1.238 (95% CI: 1.228, 1.249) and 1.178 (95% CI: 1.168, 1.189) for first osteoarthritis outpatient visits. Moreover, age at first osteoarthritis outpatient visits significantly decreased by 4.52 (95% CI: 3.45 to 5.40) days per μg/m3 for annual PM2.5 exposure at below 67.85 μg/m3. Finally, among the six constituents analyzed, black carbon appears to be the most important component associated with the association between PM2.5 exposure and the three osteoarthritis-related outcomes.

Data-driven identification of predictive risk biomarkers for subgroups of osteoarthritis using interpretable machine learning

Osteoarthritis (OA) is increasing in prevalence and has a severe impact on patients’ lives. However, our understanding of biomarkers driving OA risk remains limited. We developed a model predicting the five-year risk of OA diagnosis, integrating retrospective clinical, lifestyle and biomarker data from the UK Biobank (19,120 patients with OA, ROC-AUC: 0.72, 95%CI (0.71–0.73)). Higher age, BMI and prescription of non-steroidal anti-inflammatory drugs contributed most to increased OA risk prediction ahead of diagnosis. We identified 14 subgroups of OA risk profiles. These subgroups were validated in an independent set of patients evaluating the 11-year OA risk, with 88% of patients being uniquely assigned to one of the 14 subgroups. Individual OA risk profiles were characterised by personalised biomarkers. Omics integration demonstrated the predictive importance of key OA genes and pathways (e.g., GDF5 and TGF-β signalling) and OA-specific biomarkers (e.g., CRTAC1 and COL9A1). In summary, this work identifies opportunities for personalised OA prevention and insights into its underlying pathogenesis.

Kinematic Investigation of Healthy, Arthritic, and Postsurgery Thumbs: Is the Metacarpophalangeal Joint the Gateway to Carpometacarpal Arthritis?

The thumb carpometacarpal (CMC) joint is one of the most likely joints to develop osteoarthritis (OA). If conservative treatments fail to alleviate symptoms, surgery may be pursued. Kinematic outcomes of CMC surgery techniques have been described, but current tools have limitations in capturing motion abilities. The goals of this study were (1) develop a new and robust set of kinematic outcome measures, and apply them to (2) a cohort of younger and older control individuals without CMC OA to determine age and sex-related changes, and (3) a cohort of participants with CMC OA before, 3 months, and 6 months after undergoing thumb ligament reconstruction with tendon interposition surgery to detect the impacts of surgery. 52 (26 males, 26 females) control and 18 (3 males, 15 females) surgical participants were tested. Kinematics were investigated using motion capture by mapping the three-dimensional motion space of the whole thumb, and two-dimensional motion boundaries of the metacarpal (MC) and proximal phalange (PP). Visual analog pain score was recorded. Older control participants had shifted regions of motion compared to younger participants (p ≤ 0.027), suggesting asymptomatic CMC wear. Control females had 31% more metacarpophalangeal (MCP) motion than control males (p = 0.013), which could alter loading paths through the CMC joint and increase OA risk. Pain at 6 months postsurgery was 72% less than presurgery (p < 0.001), but motion abilities were 20-28% less than presurgery (p ≤ 0.074) and 24-40% less than control participants (p ≤ 0.066). These techniques have the possibility of identifying presymptomatic motion changes, including those at the metacarpophalangeal joint in CMC OA progression.

Metabolic syndrome increases osteoarthritis risk: findings from the UK Biobank prospective cohort study

ObjectiveThe association between Metabolic Syndrome (MetS), its components, and the risk of osteoarthritis (OA) has been a topic of conflicting evidence in different studies. The aim of this present study is to investigate the association between MetS, its components, and the risk of OA using data from the UK Biobank.MethodsA prospective cohort study was conducted in the UK Biobank to assess the risk of osteoarthritis (OA) related to MetS. MetS was defined according to the criteria set by the International Diabetes Federation (IDF). Additionally, lifestyle factors, medications, and the inflammatory marker C-reactive protein (CRP) were included in the model. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). The cumulative risk of OA was analyzed using Kaplan–Meier curves and log-rank tests. To explore potential nonlinear associations between MetS components and OA risk, a restricted cubic splines (RCS) model was employed. In addition, the polygenic risk score (PRS) of OA was calculated to characterize individual genetic risk.ResultsA total of 45,581 cases of OA were identified among 370,311 participants, with a median follow-up time of 12.48 years. The study found that individuals with MetS had a 15% higher risk of developing OA (HR = 1.15, 95%CI:1.12–1.19). Additionally, central obesity was associated with a 58% increased risk of OA (HR = 1.58, 95%CI:1.5–1.66), while hyperglycemia was linked to a 13% higher risk (HR = 1.13, 95%CI:1.1–1.15). Dyslipidemia, specifically in triglycerides (HR = 1.07, 95%CI:1.05–1.09) and high-density lipoprotein (HR = 1.05, 95%CI:1.02–1.07), was also found to be slightly associated with OA risk. When stratified by PRS, those in the high PRS group had a significantly higher risk of OA compared to those with a low PRS, whereas no interaction was found between MetS and PRS on OA risks. Furthermore, the presence of MetS significantly increased the risk of OA by up to 35% in individuals with elevated CRP levels (HR = 1.35, 95% CI:1.3–1.4).ConclusionMetS and its components have been found to be associated with an increased risk of OA, particularly in individuals with elevated levels of CRP. These findings highlight the significance of managing MetS as a preventive and intervention measure for OA.

Whole-body aging mediates the association between exposure to volatile organic compounds and osteoarthritis among U.S. middle-to-old-aged adults

BackgroundHumans are constantly exposed to various volatile organic compounds (VOCs) because of their widespread sources and characteristic of easy evaporation. Existing evidence regarding the association between VOC exposure and osteoarthritis (OA) risk is limited. PurposeThis study aimed to investigate the associations between individual urinary VOC metabolites (VOCMs) and the VOCM mixture, representing internal exposure levels of VOCs, with prevalent OA risk and to explore the mediating effect of aging and oxidative stress (OS) in these associations. MethodsData from the National Health and Nutrition Examination Surveys 2005–2020 were analyzed. Weighted generalized linear regression was employed to explore the associations between individual VOCMs and OA risk, as well as aging and OS biomarkers. A five-repeated ten-fold cross-validation elastic net model was used to identify critical VOCMs for the weight quantile sum (WQS) analysis, which was performed to explore the VOCM mixture and OA risk association. Parallel and serial mediation analyses were conducted to identify the potential mediators and mediation pathways. ResultsThis study included 6578 American adults aged ≥40 years, among whom 1052 (16.0 %) individuals reported prevalent OA. Urinary levels of N-acetyl-S-(benzyl)-L-cysteine, mandelic acid and phenylglyoxylic acid were positively associated with OA risk. Eleven VOCMs with nonzero coefficients were identified and included in the WQS analysis, and results revealed an average increase of 24.4 % in OA risk (OR = 1.244, 95 % CI: 1.041, 1.486) per one-quantile increment in the VOCM mixture. Two aging biomarkers, phenotypic age and biological age, parallelly mediated the association between the VOCM mixture and OA risk, with mediation effect proportions of 9.0 % and 16.4 %, respectively. ConclusionsExposure to VOCs is associated with an increased OA risk in middle-to-old aged American adults. The mediating effect of aging contributes to the association between co-exposure to VOCs and OA risk. Further prospective studies are required to substantiate these findings.

Potential Impact of Polymorphisms in Toll-like Receptors 2, 3, 4, 7, 9, miR-146a, miR-155, and miR-196a Genes on Osteoarthritis Susceptibility.

Osteoarthritis (OA) is a progressive inflammatory disease of synovial joints and a leading cause of disability among adults. Inflammation-related genes, including genes for Toll-like receptors (TLRs), are tightly controlled by several microRNAs that, in addition to their pivotal role in the epigenetic regulation of target genes, are ligands for TLR activation and downstream signaling. Thus, we evaluated the association between OA risk and genetic variants in TLR2, TLR3, TLR4, TLR7, TLR9, and microRNAs that regulate TLRs signaling miR146a, miR155, and miR196a2. Our study group consisted of 95 surgically treated OA patients and a control group of 104 healthy individuals. Genetic polymorphisms were determined using TaqMan real-time PCR assays (Applied Biosystems). Adjusted logistic regression analysis demonstrated that polymorphisms in TLR4 rs4986790 (OR = 2.964, p = 0.006), TLR4 rs4986791 (OR = 8.766, p = 0.00001), and TLR7 rs385389 (OR = 1.579, p = 0.012) increased OA risk, while miR-196a2 rs11614913 (OR = 0.619, p = 0.034) was significantly associated with decreased OA risk. Our findings indicate that polymorphisms in the TLR4 and TLR7 genes might increase OA risk and suggest a novel association of miR-196a2 polymorphism with decreased OA susceptibility. The modulation of TLRs and miRNAs and their cross-talk might be an attractive target for a personalized approach to OA management.

Associations of childhood-to-adulthood body size trajectories and genetic susceptibility with the risks of osteoarthritis: a population-based cohort study of UK Biobank data

BackgroundLarge adulthood body size was associated with increased risk of osteoarthritis. We aimed to examine the association between body size trajectories from childhood to adulthood and potential interactions with genetic susceptibility on osteoarthritis risk. MethodsWe included participants from the UK Biobank aged 38–73 years in 2006–10. Childhood body size information was collected by questionnaire. Adulthood BMI was assessed and transformed into three categories (<25 kg/m2 for normal, 25–29·9 kg/m2 for overweight, and >30 kg/m2 for obesity). A Cox proportional hazards regression model was applied to assess the association between body size trajectories and osteoarthritis incidence. Osteoarthritis-related polygenic risk score (PRS) was constructed to evaluate its interactions with body size trajectories on osteoarthritis risk. FindingsFor the 466 292 participants included, we identified nine body size trajectories [thinner to normal (11·6%), overweight (17·2%), or obesity (26·9%); average to normal (11·8%), overweight (16·2%), or obesity (23·7%); and plumper to normal (12·3%), overweight (16·2%), or obesity (23·6%)]. Compared with individuals in the average-to-normal group, all other trajectory groups had higher risks of osteoarthritis, after adjustment for demographic, social-economic and lifestyle covariates (hazard ratios [HRs] 1·05–2·41; all p<0·01). Among them, thinner-to-obesity (HR 2·41; 95% CI 2·23–2·49) had the most prominent association with increased osteoarthritis risk. A high PRS was significantly associated with an increased risk of osteoarthritis (1·14; 1·11–1·16), whereas no interaction between childhood-to-adulthood body size trajectories and PRS on osteoarthritis risks was observed. The population attributable fraction suggested that body size towards normal in adulthood could eliminate osteoarthritis cases by 18·67% for thinner-to-overweight to 38·74% for plumper-to-obesity. InterpretationAverage-to-normal body size seems to be the healthiest childhood-to-adulthood trajectory for osteoarthritis risk, whereas a trajectory of increased body size from thinner to obesity has the highest risk for osteoarthritis. These associations are independent of osteoarthritis genetic susceptibility. FundingThe National Natural Science Foundation of China (32000925) and Guangzhou Science and Technology Program (202002030481).

Physical activity patterns, genetic susceptibility, and risk of hip/knee osteoarthritis: a prospective cohort study based on the UK Biobank

The effect of physical activity on hip/knee osteoarthritis (OA) and how it varies by genetic susceptibility to OA remains inconclusive. In a cohort study of UK Biobank, 436,166 OA-free participants were recruited in 2006-2010 and followed for knee/hip OA until the end of 2020. 28 physical activity-related items were collected at baseline. Cox regression was used to estimate associations between physical activity behaviors, as well as major activity patterns (i.e., significant principal components[PCs] identified by principal component analysis), and risk of OA, adjusting for multiple confounders. We further stratified the analyses by polygenic risk score (PRS) for OA to examine the impact of genetic susceptibility to OA on the studied association. During a mean follow-up of 11.15 years, 13,227 hip and 21,119 knee OA cases were identified. 19, out of 28, studied items showed associations with increased OA risk. Compared with low adherence group(<1st tertile of PC score for each pattern), individuals with high adherence to five identified patterns were associated with increased risk of OA. The moderate adherence to "strenuous sports"(HR=0.93, 95%CI: 0.89-0.97) and "walking for pleasure"(HR=0.93, 95%CI: 0.89-0.98) patterns was associated with reduced OA. Similar risk patterns were obtained in the stratified analysis by PRS levels for OA. High intensity of most activity patterns were associated with increased OA. However, a protective effect was suggested for moderate adherence to patterns of "strenuous sports" and "walking for pleasure" that consistent across different genetic susceptibilities, underscoring the potential benefits of moderate-intensity physical activity on OA.

Tetra-primers ARMS-PCR Based Association Analyses of Synonymous and Intronic Variants in the ADAM12 Gene with Susceptibility to Knee Osteoarthritis: A Case-Control Study.

Genetic variations in a disintegrin and metalloprotease 12 (ADAM12) gene may contribute to develop Osteoarthritis (OA) that is characterized by cartilage matrix degradation and osteophytes formation. Therefore, the aim of present study was to analyze the association between the ADAM12 gene variants and knee OA predisposition. Tetra-primers ARMS-PCR was employed, to genotype the ADAM12 gene polymorphisms (rs1044122 and rs1871054) in 400 knee OA patients and equal number of age-matched controls. The association between ADAM12 gene variants and OA susceptibility was estimated using the Chi-square, logistic regression, haplotypes and linkage analyses. A significant association of rs1044122 (genotype: χ2 = 18.94; P < 0.001, allele: χ2 = 19.10; P < 0.001) and rs1871054 (genotype: χ2 = 10.04; P = 0.007, allele: χ2 = 10.57; P = 0.001) was observed with increased OA susceptibility. The variant genotype of rs1044122 increased OA risk more than twice [odds ratio (OR) 2.20; P = 0.001] and the risk was higher in females (OR 2.43; P = 0.001). The variant genotype of rs1871054 was perceived to almost double the risk in females (OR 1.97; P = 0.003). Moreover, a significant association of rs1044122 and rs1871054 under the additive genetic model (P < 0.001 and P = 0.002, respectively) was observed. The targeted ADAM12 gene polymorphisms, showed significant association with knee OA susceptibility. Females harboring the polymorphisms might be at risk. Besides, the haplotype CC of rs1044122 and rs1871054 in the ADAM12 gene may double knee OA risk. These findings may help in determining the etiology of OA and recognizing the people at risk of developing knee OA.

The effects of orthopedic pathological conditions and systemic diseases on the prevalence of hip osteoarthritis in Modern African- and European-Americans.

Osteoarthritis (OA) is a leading cause of disability among aging adults. In the U.S., many individuals living with total hip replacements attribute OA as the cause. However, the majority of anthropological OA research excludes pathological individuals (i.e., individuals with systemic disease, traumatic injuries, or orthopedic devices). Thus, little is known about how implants and pathological conditions impact OA beyond a general acceptance that they likely increase OA risk. This study adds to the skeletal research surrounding OA by directly investigating its relationship with age, disease, and implants. The proximal femora of 186 African- and European-American individuals (21-95 years old) from the Edmonds Orthopedic Pathology Collection (National Museum of Health and Medicine; Armed Forces Institute of Pathology) were analyzed. The individuals were grouped into three cohorts: disease; non-disease; and previous injury/implant. Jurmain's (1990) ordinal scoring method was used to categorize OA changes as: none/slight; moderate; severe; and ankylosis. Intra-rater reliability for the scoring of OA was perfect, while inter-rater reliability was moderate. Results from Chi-square tests, exploratory data analysis, and ordinal logistic regression showed that there was a statistically significant relationship (p < 0.001) between degree of OA, age, recorded disease (e.g., cancer), and evidence of previous injury (i.e., healed fractures, fracture fixation devices). In contrast with the expectation that different populations exhibit different patterns of OA, no significant sex or ancestry effects were observed. These results help researchers better understand the etiology and contemporary risk factors of OA as well as identifying an additional subset of the population who may be at greater risk for developing OA - i.e., individuals with fractures, implants, and systemic disease, especially those in older age cohorts (60+ years).

Association Between Osteoarthritis and Water Fluoride Among Tongyu Residents, China, 2019: a Case-Control of Population-Based Study.

Fluoride is an environmental chemical that has adverse effects on articular cartilage, probably increasing osteoarthritis (OA) risk. However, this association still needs more epidemiological evidence to clarify. The aim of this study was to determine the relationships between chronic fluoride exposure and OA risk among the residents living in Tongyu County, China, 2019, with a frequency-matched case-control study (186 OA patients and 186 healthy participants). The results showed that urinary fluoride (UF) (2.73 ± 1.18mg/L) was significantly higher in OA patients compared to the controls (2.35 ± 1.24mg/L) (p < 0.002). After adjustment, the odds ratios (ORs) with 95% confidence intervals (95% CIs) between the OA risk and fluoride were calculated by the unconditional logistic regression. In full sample analysis, a 1mg/L increase in UF level was associated with a 27% higher risk of OA (1.06-1.52, p = 0.008), and 4th quarter's participants were associated with higher risk when compared to 1st quarter (OR: 2.46, 95% CI: 1.34-4.57, p = 0.003). In stratified analysis, compared to 1st quarter, 4th quarter's participants were 4 times more likely to have OA (1.86-8.82, p < 0.001) in the non-obese group and 7.7 times more likely to have OA (2.58-25.05, p < 0.001) among adults ≤ 60years. In conclusion, excessive exposure of water fluoride may increase OA risk, and could have more impact on the specific population such as non-obese, and adult aged ≤ 60years.

Can we afford to ignore the biology of joint healing and graft incorporation after ACL reconstruction?

Anterior cruciate ligament (ACL) reconstruction is successful at restoring stability to return ACL injured patients to high-demand work, sports, and recreational activities. The development of posttraumatic osteoarthritis (OA) in roughly half of patients just 10-15 years after ACLR highlight the need to improve clinical care pathways. Graft failure and reinjury rates, which further increase OA risk, also remain high for younger and more active patients. The biological components of joint recovery and graft incorporation, therefore, impact short- and long-term clinical outcomes. Biochemical and magnetic resonance imaging (MRI) data show substantial compromise of articular cartilage metabolism and matrix composition after ACL injury and reconstructive surgery suggesting a potential need for activity modulation in early recovery. Furthermore, joint recovery is variable with compositional MRI studies showing progressive cartilage degeneration 1 and 2 years after ACLR. Biopsy and MRI studies also show high variability in ACL graft characteristics within the 1st year after ACLR followed by continued graft maturation into the 2nd year and beyond. To improve the care of ACL injured patients, there is a critical need for clinical attention and scientific inquiry into timing the reintroduction of higher load activities in relationship to neuromuscular recovery, joint biology, and graft maturation. In addition to symptomatic and mechanical recovery, development and validation of biological markers for joint and cartilage homeostasis as well as ACL graft healing are needed for personalized decision making on rehabilitation needs, reduction of OA risk, and resumption of athletic, recreational, and vocational activities.

Visualizing pre-osteoarthritis: Integrating MRI UTE-T2* with mechanics and biology to combat osteoarthritis-The 2019 Elizabeth Winston Lanier Kappa Delta Award.

Osteoarthritis (OA) is a leading cause of pain and disability for which disease-modifying treatments remain lacking. This is because the symptoms and radiographic changes of OA occur after the onset of likely irreversible changes. Defining and treating earlier disease states are therefore needed to delay or to halt OA progression. Taking this concept a step further, studying OA pathogenesis before disease onset by characterizing potentially reversible markers of increased OA risk to identify a state of "pre-osteoarthritis (pre-OA)" shifts the paradigm towards OA prevention. The purpose of this review is to summarize the 42 studies comprising the 2019 Kappa Delta Elizabeth Lanier Award where conceptualization of a systems-based definition for "pre-osteoarthritis (pre-OA)" was followed by demonstration of potentially reversible markers of heightened OA risk in patients after anterior cruciate ligament (ACL) injury and reconstruction. In the process, these efforts contributed a new magnetic resonance imaging method of ultrashort echo time (UTE) enhanced T2* mapping to visualize joint tissue damage before the development of irreversible changes. The studies presented here support a transformative approach to OA that accounts for interactions between mechanical, biological, and structural markers of OA risk to develop and evaluate new treatment strategies that can delay or prevent the onset of clinical disease. This body of work was inspired by and performed for patients. Shifting the paradigm from attempting to modify symptomatic radiographic OA towards monitoring and reversing markers of "pre-OA" opens the door for transforming the clinical approach to OA from palliation to prevention.

Excessive downhill training leads to early onset of knee osteoarthritis

Increased levels of pro-inflammatory cytokines are associated with the release of degradative enzymes leading to osteoarthritis (OA) development. Although physical exercise (PE) is generally recognized as beneficial for OA symptoms, excessive training workload and eccentric muscular exercise have increased OA risk. Here, we investigated the effects of excessive exercise workload and exercise type on systemic inflammation and knee joint OA. Mice were divided into five groups: sedentary (SED), uphill training (TRU), downhill training (TRD), excessive uphill training (ETU), and excessive downhill training (ETD) for an 8-week training intervention protocol. ETD group had increased pro-inflammatory cytokines in serum, vastus lateralis (VL), and vastus medialis (VM) muscles, while ETU group mice had increased cytokine levels in the VL and VM. Total knee joint OARSI score were more significant in ETD group compared to SED and TRU groups. They were also more meaningful for the medial tibial plateau of ETD group compared to SED group. MMP-3 and cleaved Caspase-3 were higher in the ETD group than the SED and TRU group, while Adamts-5 was higher in the ETD group than the SED group. TRU group had increased PRG-4 levels compared to ETU and ETD group. ETD group had decreased total bone volume, trabecular bone volume, and cortical thickness compared to SED group. Excessive downhill training induced a chronic pro-inflammatory state in mice and was associated with early signs of cartilage and bone degeneration that are clinical indicators of knee OA.

Impact of parity on biomechanical risk factors for knee OA initiation

BackgroundWomen are twice as likely as men to develop knee osteoarthritis (OA), and with it experience greater losses of physical function and disability. A change in the mechanical environment of the joint is a key initiating factor for knee OA. Differences in morphology, joint injury risk, and hormonal shifts in mid-life are often considered factors which increase OA risk for women. Pregnancy, a time of significant hormonal, morphological, and biomechanical change, has received comparably less attention. If morphological and biomechanical changes persist postpartum, this could increase OA risk for parous (childbearing) women. Research questionAre lower limb gait mechanics different between healthy nulliparous (non-childbearing) and parous (childbearing) women? MethodsTwenty-eight self-reported not pregnant female participants (14 parous, 14 nulliparous) were recruited for the study. Nulliparous participants had never given birth to a child. Parous participants had given birth to at least one full-term infant (37–42 weeks) without complications between one to five years before data collection. Motion capture of participants’ preferred, fast, and set (1.4 m/s) walking speeds was conducted. Repeated measures ANOVA were performed to test for significant group differences in joint kinematics and kinetics. ResultsThere was a significant main effect of group indicating a larger knee flexion angle at toe off (p = 0.0002), smaller knee extension moment at heel strike (p = 0.0006), smaller first peak knee flexion moment (p = 0.040), and smaller peak hip adduction moment for the parous group compared to the nulliparous group (p = 0.003). Static Q-angle did not differ between groups. SignificanceAlteration in mechanics from the habitual loading pattern are thought to increase risk of OA. Smaller knee moments in post-partum women could alter the mechanical stimulus to cartilage, and should be investigated in conjunction with cartilage health measures to determine the link with OA initiation.

Interleukin 13 (IL-13)-regulated expression of the chondroprotective metalloproteinase ADAM15 is reduced in aging cartilage

ObjectiveThe adamalysin metalloproteinase 15 (ADAM15) has been shown to protect against development of osteoarthritis in mice. Here, we have investigated factors that control ADAM15 levels in cartilage. DesignSecretomes from wild-type and Adam15−/− chondrocytes were compared by label-free quantitative mass spectrometry. mRNA was isolated from murine knee joints, either with or without surgical induction of osteoarthritis on male C57BL/6 mice, and the expression of Adam15 and other related genes quantified by RT-qPCR. ADAM15 in human normal and osteoarthritic cartilage was investigated similarly and by fluorescent immunohistochemistry. Cultured HTB94 chondrosarcoma cells were treated with various anabolic and catabolic stimuli, and ADAM15 mRNA and protein levels evaluated. ResultsThere were no significant differences in the secretomes of chondrocytes from WT and Adam15−/− cartilage. Expression of ADAM15 was not altered in either human or murine osteoarthritic cartilage relative to disease-free controls. However, expression of ADAM15 was markedly reduced upon aging in both species, to the extent that expression in joints of 18-month-old mice was 45-fold lower than in that 4.5-month-old animals. IL-13 increased expression of ADAM15 in HTB94 ​cells by 2.5-fold, while modulators of senescence and autophagy pathways had no effect. Expression of Il13 in the joint was reduced with aging, suggesting this cytokine may control ADAM15 levels in the joint. ConclusionExpression of the chondroprotective metalloproteinase ADAM15 is reduced in aging human and murine joints, possibly due to a concomitant reduction in IL-13 expression. We thus propose IL-13 as a novel factor contributing to increased osteoarthritis risk upon aging.

Role of IL-17 gene polymorphisms in osteoarthritis: A meta-analysis based on observational studies.

Osteoarthritis (OA) is a chronic complex multifactorial joint disease, and a major degenerative form of arthritis. Existing studies on the association between polymorphisms of the IL-17 gene and the risk of OA in different populations have yielded conflicting findings. To investigate the association between polymorphisms of the IL-17 gene and the risk of OA. We conducted a meta-analysis by systematically searching databases, including PubMed, EMBASE, MEDLINE, Cochrane Library, and Google Scholar to evaluate this association by calculating pooled odds ratios with 95% confidence intervals. Moreover, subgroup analyses stratified by ethnicity and OA type were also conducted. In a total of 6 citations involving 8 studies (2131 cases and 2299 controls), 4 single nucleotide polymorphisms were identified. Of these 4 polymorphisms, 2 (rs2275913, rs763780) were common in five case-control studies. Together, the pooled results revealed that the A allele and genotype AA/GA of the rs2275913 polymorphism, and the C allele and genotype CC of the rs763780 polymorphism in the IL-17 gene increased the risk of OA. Furthermore, stratification analyses by ethnicity and OA type showed that the rs2275913 polymorphism increased the risk of OA among Asians and in knee/hip OA, respectively. In addition, stratification analyses also revealed that the rs763780 polymorphism increased OA risk among both Asians and Caucasians in knee/hip OA. The rs763780 polymorphism of the IL-17F gene increased the risk of OA, whereas the rs2275913 polymorphism of the IL-17A gene increased the risk of OA only among Asians. Due to the limitations of this study, these findings should be validated in future studies.

Correction: MMP-3 gene polymorphisms are associated with increased risk of osteoarthritis in Chinese men.

[This corrects the article DOI: 10.18632/oncotarget.18493.].

Defining the factors that alter OA risk following ACL injury using pre-clinical animal models

Purpose: Osteoarthritis (OA) is a common long-term outcome of anterior cruciate ligament (ACL) injuries, but still only ∼50% of ACL deficient knees develop OA. Concomitant meniscal or chondral damage substantially increases OA risk, however factors affecting OA development in isolated ACL tears are less defined. There is evidence to suggest that the impact at the time of ACL injury may be an important risk factor in addition to altered joint mechanics. The aim of this study was to investigate changes in joint mechanics, pain behaviours and OA pathogenesis in models of isolated ACL injury comparing minimal impact trauma (surgical transection) with compression induced ligament failure (mechanical rupture). Methods: Ten-week-old, male C57BL/6 mice were randomised into 4 groups: 1) uninjured, 2) sham surgery, 3) surgical ACL transection (ACLT), or 4) mechanical ACL rupture (mACLR). Outcomes were measured at 1, 2, 4 and 8 weeks post-injury. Ex vivo knee mechanics (range of motion and joint stiffness) were measured using an anterior-posterior (AP) laxity tester (n = 6/group). Pain behaviour was assessed using von Frey filaments (mechanical allodynia) or an incapacitance tester (static weight-bearing) and included pre-injury tests (n = 6/group). OA severity in the medial and lateral tibiofemoral compartments was scored histologically for: proteoglycan loss, cartilage structural damage, osteophyte development, subchondral bone sclerosis and synovitis (n = 7/group). Results: ACL injury significantly altered the mechanics of the knee whilst sham surgery did not differ from uninjured joints. AP range of motion increased equally (3-fold) following ACLT and mACLR (P < 0.02), with no improvement up to 8 weeks post-injury. Anterior joint stiffness increased over time in controls. ACLT stiffness was significantly lower than sham at 1 and 2 weeks post-injury (P < 0.02) with some recovery at 4 weeks, whilst mACLR remained largely unchanged but significantly less than uninjured at 4 and 8 weeks post-injury (P < 0.01). Significant mechanical allodynia was equally evident at all time points following sham surgery, ACLT and mACLR (P < 0.001 vs pre-injury). In contrast, weight-bearing was only reduced in ACL injured limbs (1–8 weeks post-injury, P < 0.01 vs pre-injury both ACLT and mACLR). OA pathology was found in both the medial and lateral compartments, but was substantially worse in the former. Differences between the two ACL injury models were also more evident medially. The development and progression of medial cartilage pathology was slower following ACLT compared to mACLR: proteoglycan loss and cartilage damage were not significantly increased until 8 weeks post-ACLT (P < 0.005) whilst mACLR induced significant changes by week 2 (P < 0.001). Similarly, significant osteophyte formation was not evident until 8 weeks post-ACLT (P < 0.005) but was present 1 week after mACLR (P < 0.005). Subchondral bone sclerosis was elevated following mACLR but was not significantly different from ACLT or controls. Synovitis was greatest following ACLT at 1 week post-injury (P < 0.005) but was no different between ACLT, mACLR and sham surgery from 2–4 weeks. At 8 weeks, sham surgery synovitis had returned to uninjured levels whilst ACLT and mACLR remained slightly elevated (P < 0.005). Conclusions: These results show that loss of ACL integrity, irrespective of the mechanism of injury, causes severely altered joint mechanics and increased pain responses. Despite these functional and symptomatic similarities, pathological progression of disease was vastly different between the two models. ACL transection results in a slowly progressive OA whilst compressive rupture induces rapid onset and progression. These findings indicate that pain and anterior–posterior joint mechanics are not predictive of OA severity but the acute trauma itself can significantly influence the outcome of disease. Defining ways to determine compressive loading experienced at the time of ACL injury, could improve prediction of OA risk and patient management.

Genetic polymorphism in the asporin gene is not a key risk factor for osteoarthritis: Evidence based on an updated cumulative meta-analysis.

To provide an evidence-based medical basis for the treatment of osteoarthritis, a meta-analysis was performed to assess the association between asporin (ASPN) gene polymorphism and susceptibility to osteoarthritis (OA). The current study searched the literature from January 1st, 1915 through February 1st, 2017 using the Cochrane Library, PubMed, the Excerpta Medica database (EMBASE) and three main Chinese databases (VIP, CNKI and Wan Fang). Cohort and case-control studies that explored the association between different types of ASPN alleles and OA susceptibility were evaluated. The K/L grading system, clinical and radiological diagnoses were used for OA diagnosis. A random-effects model was used in a pooled analysis to adjust for heterogeneity of the included studies, and the differences between treatment groups were reported as odds ratio (OR), 95% confidence intervals (CIs) and P-values. Begg's funnel plots and Egger's tests were used to assess publication bias in the present meta-analysis. Following document retrieval and screening, a total of 10 studies were deemed eligible, including 4,842 patients and 3,661 healthy subjects. Results of the multivariate meta-regression analysis revealed that the study sample size was a source of heterogeneity between studies. The D17 allele was a risk factor for the development of OA (OR=1.33, 95% CI: 1.02–1.73, P<0.05). The other alleles were not considered as risk factors for development of OA (P>0.05). The results of the meta-analysis verified that ASPN polymorphisms were not significantly relevant to an increased OA risk. However, the mechanisms contributing to the association between ASPN polymorphisms and OA risk still require further study.