Risk Factor For Osteoarthritis Research Articles

Changes in gastrocnemius MTU stiffness and their correlation with plantar pressure in patients with knee osteoarthritis

BackgroundAbnormal, excessive, and repetitive knee load is a critical risk factor for osteoarthritis (OA). The gastrocnemius muscle-tendon unit (MTU) interacts with foot biomechanics and is vital in cushioning the knee load. Abnormal gastrocnemius activation and plantar pressure during walking in patients with knee OA may negatively affect gastrocnemius MTU stiffness, increasing knee load. Few studies investigated the relationship between gastrocnemius MTU stiffness and plantar pressure. This study aimed to evaluate the changes in gastrocnemius MTU stiffness in patients with knee OA and their correlations with plantar pressure and clinical symptoms.MethodsThirty women patients with unilateral knee OA and 30 healthy women participants were recruited. Shear wave elastography was used to quantify gastrocnemius MTU stiffness in ankle resting and anatomical 0° positions, defined as natural and neutral positions in this study. A plantar pressure analysis system was used to collect the plantar pressure parameters on the symptomatic side in patients with knee OA. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Visual Analogue Scale (VAS) scores were used to measure the severity of clinical symptoms.ResultsMedial and lateral gastrocnemius (MG and LG) stiffness on both the asymptomatic and symptomatic sides in patients with knee OA was increased compared with that in healthy participants. The MG and LG optimal cutoff stiffness in the natural position was 15.73 kPa and 14.25 kPa, respectively. The optimal cutoff stiffness in the neutral position was 36.32 kPa and 25.43 kPa, respectively, with excellent sensitivity and specificity. The MG and LG stiffness were positively correlated with the percentages of anterior and medial plantar pressure and negatively correlated with the length of pressure center path. The LG and MG were significantly correlated with WOMAC and VAS scores.ConclusionPatients with knee OA have increased gastrocnemius muscle stiffness, closely related to plantar pressure and clinical symptoms. Monitoring the gastrocnemius muscle in patients with knee OA can provide an essential basis for its prevention and treatment.

Metalloproteins as risk factors for osteoarthritis: improving and understanding causal estimates using Mendelian randomization.

Osteoarthritis (OA) is one of the most prevalent musculoskeletal disorders and a primary cause of pain and disability among the elderly population. Research on the relationship between metalloproteins (MPs) and OA is limited, and causality remains unclear. Our objective is to utilize Mendelian randomization (MR) to explore the possible causal relationship between MPs and OA. The data on MPs were derived from a Genome-Wide Association Study (GWAS) analysis involving 3301 samples. The GWAS data for OA were obtained from an analysis involving 462,933 European individuals. In this study, a variety of two-sample Mendelian randomization methods (two-sample MR) to evaluate the causal effect of MPs on OA, including inverse variance weighted method (IVW), MR-Egger method, weighted median method (WM), simple mode, weight mode, and Wald ratio. The primary MR analysis using the IVW method reveals a significant negative correlation between Metallothionein-1F (MT-1F), zinc finger protein 134 (ZNF134), calcium/calmodulin-dependent protein kinase type 1D (CAMK1D), and EF-hand calcium-binding domain-containing protein 14 (EFCAB14) with the occurrence of osteoarthritis (OA) (p value < 0.05). However, no causal relationship was observed in the opposite direction between these MPs and OA. Notably, even in combined models accounting for confounding factors, the negative association between these four MPs and OA remained significant. Sensitivity analysis demonstrated no evidence of horizontal pleiotropy or heterogeneity, and leave-one-out analysis confirmed the robustness of the results. In this study, we have established a conspicuous association between four distinct MPs and OA. This discovery augments our understanding of potential avenues for the diagnosis and treatment of this condition. Key Points • The MR method was employed to assess the relationship between MPs and OA. • A total of four types of MPs have demonstrated inhibitory effects on the occurrence of OA.

Effect of prebiotic fiber on physical function and gut microbiota in adults, mostly women, with knee osteoarthritis and obesity: a randomized controlled trial.

Obesity is a primary risk factor for knee osteoarthritis (OA). Prebiotics enhance beneficial gut microbes and can reduce body fat and inflammation. Our objective was to examine if a 6-month prebiotic intervention improved physical function in adults with knee osteoarthritis and obesity. We also measured knee pain, body composition, quality of life, gut microbiota, inflammatory markers, and serum metabolomics. Adults (n = 54, mostly women) with co-morbid obesity (BMI > 30kg/m2) and unilateral/bilateral knee OA were randomly assigned to prebiotic (oligofructose-enriched inulin; 16g/day; n = 31) or isocaloric placebo (maltodextrin; n = 21) for 6months. Performance based-tests, knee pain, quality of life, serum metabolomics and inflammatory markers, and fecal microbiota and short-chain fatty acids were assessed. Significant between group differences were detected for the change in timed-up-and-go test, 40m fast paced walk test, and hand grip strength test from baseline that favored prebiotic over placebo. Prebiotic also reduced trunk fat mass (kg) at 6months and trunk fat (%) at 3months compared to placebo. There was a trend (p = 0.059) for reduced knee pain at 6months with prebiotic versus placebo. In gut microbiota analysis, a total of 37 amplicon sequence variants differed between groups. Bifidobacterium abundance was positively correlated with distance walked in the 6-min walk test and hand grip strength. At 6months, there was a significant separation of serum metabolites between groups with upregulation of phenylalanine and tyrosine metabolism with prebiotic. Prebiotics may hold promise for conservative management of knee osteoarthritis in adults with obesity and larger trials are warranted. Clinicaltrials.gov/study/NCT04172688.

Association Between Sleep Apnea Syndrome and Osteoarthritis: Insights from Bidirectional Mendelian Randomization and Bioinformatics Analysis.

Sleep apnea syndrome(SAS) and osteoarthritis (OA) are two prevalent diseases that often coexist, but the causal relationship between them remains unclear. In light of this, our team utilizes Mendelian Randomization and bioinformatics analysis methods to investigate the potential association between the two diseases. In this study, we utilized GWAS data pertaining to SAS and OA to assess the causal relationship between the two diseases through Mendelian randomization (MR) analysis. We then employed transcriptomic data to perform differential gene identification, WGCNA, shared gene determination, functional enrichment analysis, and colocalization analysis, all designed to further elucidate the mechanisms underlying the association between the two diseases. In the end, we utilized Mendelian randomization (MR) analysis again to delve deeper into the relationship between the two diseases and immune cells. Our research findings indicate that SAS is a risk factor for OA (p = 0.000004), knee OA (p = 0.0000001) and hip OA(p = 0.001). Furthermore, OA (p = 0.000195), knee OA (p = 0.001) are significant risk factors for SAS. However, there is no clear evidence that hip OA (p = 0.892) is a risk factor for SAS. Interestingly, the genes shared between OA and SAS are significantly enriched in leukocyte migration, leukocyte chemotaxis. Moreover, colocalization analysis suggests that the genes JUNB, COL8A1, FOSB, and IER2 may be key genes associated with both diseases. Furthermore, 57 immune cell phenotypes are associated with SAS, 95 with OA, and 6 shared between both diseases. This research confirmed the bidirectional causal relationship between SAS and OA. Notably, the 4 genes (JUNB, COL8A1, FOSB, IER2) and 6 immune phenotypes are crucial for both diseases, these provide hopeful targets for future interventions against these two diseases.

Association between Sarcopenic Obesity and Knee Osteoarthritis: A Narrative Review

Sarcopenia and obesity have been studied independently as risk factors for knee osteoarthritis. However, there is now research interest in investigating whether the co-existence of sarcopenia and obesity (sarcopenic obesity) within the same individual significantly increases the risk of knee osteoarthritis, compared to sarcopenia or obesity alone. This review synthesises current literature to explore the association between sarcopenic obesity and knee osteoarthritis, emphasising both the clinical evidence and existing gaps. We highlight the challenges and progress in defining sarcopenic obesity and discuss the impact that the lack of a consensus definition of sarcopenic obesity has on comparing outcomes of studies investigating the relationship between sarcopenic obesity and knee OA. We offer methodological insights to guide future studies investigating whether sarcopenic obesity increases the risk of knee osteoarthritis above and beyond the risk associated with each condition on its own. The implications for clinical practice are discussed, including the need to incorporate effective resistance exercise into weight loss programs for individuals with sarcopenic obesity. This is critical as a general weight loss program alone among individuals with sarcopenic obesity can include substantial loss of muscle mass, potentially predisposing patients to further functional decline.

Unilateral high-riding vertebral artery is associated with asymmetric morphological changes of the atlantoaxial joint: a novel risk factor for atlantoaxial osteoarthritis.

This study aimed to investigate the association between unilateral high-riding vertebral artery (HRVA) and morphological changes in the atlantoaxial joint (AAJ) and to determine whether unilateral HRVA is a risk factor for atlantoaxial osteoarthritis (AAOA). We conducted a retrospective analysis of 2496 patients admitted to our medical center between January 2020 and December 2022 who underwent CT imaging of the cervical spine. Two hundred and seventy-two patients with unilateral HRVA (HRVA group) were identified and a respective 2:1 age- and sex-matched control group without HRVA was built. Morphological parameters, including C2 lateral mass settlement (C2 LMS), C1/2 coronal inclination (C1/2 CI), lateral atlanto-dental interval (LADI), and C1/2 relative rotation angle (C1/2 RRA) were measured. The degree of AAOA was recorded. Risk factors associated with AAOA were identified using univariate and multivariable logistic regression analyses. The study included 61.4% women, and the overall average age of the study population was 48.7years. The morphological parameters (C2 LMS, C1/2 CI, and LADI) in AAJ were asymmetric between the HRVA and the non-HRVA sides in the HRVA group (p < 0.001). These differences in parameters (d-C2 LMS, d-C1/2 CI, and d-LADI) between the HRVA and the non-HRVA sides, and C1/2 RRA were significantly larger than those in the control group. Eighty-three of 816 patients (10.2%) with AAOA had larger values of d-C2 LMS, d-C1/2 CI, d-LADI, and C1/2 RRA compared with the patients without AAOA (p < 0.05). The multivariable logistic regression analysis indicated that unilateral HRVA [adjusted odds ratio (OR) = 2.6, 95% CI: 1.1-6.3, p = 0.029], age in the sixth decade or older (adjusted OR = 30.2, 95% CI: 16.1-56.9, p < 0.001), women (adjusted OR = 2.1, 95% CI: 1.0-5.6, P = 0.034) were independent risk factors for AAOA. Unilateral HRVA was associated with asymmetric morphological changes of nonuniform settlement of C2 lateral mass, lateral slip of atlas, and atlantoaxial rotation displacement. Besides age ≥ 60years and females, unilateral HRVA is an independent risk factor for AAOA.

Prevalence and Risk Factors of Osteoarthritis in Korea: A Cross-Sectional Study.

Background and Objectives: The goal of this study is to determine the prevalence of knee osteoarthritis (OA) and risk factors for the disease in Korean adults over the age of 50, as well as to provide basic data for OA prevention through management. Materials and Methods: Based on 2010-2013 data from the Korean National Health and Nutrition Survey, 7962 adults over the age of 50 who participated in radiological tests and health surveys for the diagnosis of osteoarthritis were chosen as participants. Results: The risk factors for OA occurrence were investigated using complex sample multiple logistic regression analysis. According to the findings, the prevalence of knee OA in Korea was 33.3% in this study, with the risk of OA being higher in women, the elderly, people with a lower education level, and people with obesity. Conclusions: To reduce the incidence of OA, interventions and lifestyle changes are needed to prevent the onset of disease in participants with risk factors for OA, such as older women, low education levels, and obesity.

Metformin inhibits knee osteoarthritis induced by type 2 diabetes mellitus in rats: S100A8/9 and S100A12 as players and therapeutic targets

Abstract Type 2 diabetes mellitus (T2DM) is a significant risk factor for osteoarthritis (OA), and metformin, as the main therapeutic drug for T2DM, has shown positive effects on OA without a clear mechanism. This study aimed to explore the protective effects and mechanisms of oral metformin in T2DM-induced OA. We identified differentially expressed genes, using the GSE117999 and GSE98918 datasets, and protein–protein interaction networks were analyzed using the MCODE algorithm in cytospace to finalize the OA hub genes (S100A8, S100A9, and S100A12). To validate whether S100A8, S100A9, and S100A12 are potential targets of action for OA, we randomly divided 40 SD rats into a control group (CG, n = 10) and a T2DM group (n = 30). We modeled rats in the T2DM group with streptozotocin (35 mg/kg, i.p.) and a high carbohydrate and fat diet. Finally, 20 were randomly selected and divided into the T2DM group (n = 10) and the treated group (Met + T2DM, n = 10), and the treated group was given Met (180 mg/kg/day) by gavage for 8 weeks. We subsequently used histological assessment to show that oral metformin mitigated the development of T2DM-associated OA as indicated by the OA Research Society International score and articular cartilage thickness, and immunohistochemistry also confirmed that metformin significantly reduced the expression of S100A8, S100A9, and S100A12 in the knee joints of OA rats. In conclusion, metformin demonstrated a protective effect against OA in T2DM-induced rats, slowing knee OA progression by inhibiting S100A8, S100A9, and S100A12 expression. These findings suggest potential biological targets for future OA treatments.

The Genetic Markers of Knee Osteoarthritis in Women from Russia.

Osteoarthritis is a chronic progressive joint disease that clinically debuts at the stage of pronounced morphologic changes, which makes treatment difficult. In this regard, an important task is the study of genetic markers of the disease, which have not been definitively established, due to the clinical and ethnic heterogeneity of the studied populations. To find the genetic markers for the development of knee osteoarthritis (OA) in women from the Volga-Ural region of Russia, we conducted research in two stages using different genotyping methods, such as the restriction fragment length polymorphism (RFLP) measurement, TaqMan technology and competitive allele-specific PCR-KASPTM. In the first stage, we studied polymorphic variants of candidate genes (ACAN, ADAMTS5, CHST11, SOX9, COL1A1) for OA development. The association of the *27 allele of the VNTR locus of the ACAN gene was identified (OR = 1.6). In the second stage, we replicated the GWAS results (ASTN2, ALDH1A2, DVWA, CHST11, GNL3, NCOA3, FILIP/SENP1, MCF2L, GLT8D, DOT1L) for knee OA studies. The association of the *T allele of the rs7639618 locus of the DVWA gene was detected (OR = 1.54). Thus, the VNTR locus of ACAN and the rs7639618 locus of DVWA are risk factors for knee OA in women from the Volga-Ural region of Russia.

The biomechanical influence of transtibial Bone-Anchored limbs during walking

Individuals with unilateral transtibial amputation (TTA) using socket prostheses demonstrate asymmetric joint biomechanics during walking, which increases the risk of secondary comorbidities (e.g., low back pain (LBP), osteoarthritis (OA)). Bone-anchored limbs are an alternative to socket prostheses, yet it remains unknown how they influence multi-joint loading. Our objective was to determine the influence of bone-anchored limb use on multi-joint biomechanics during walking. Motion capture data (kinematics, ground reaction forces) were collected during overground walking from ten participants with unilateral TTA prior to (using socket prostheses) and 12-months after bone-anchored limb implantation. Within this year, each participant completed a rehabilitation protocol that guided progression of loading based on patient pain response and optimized biomechanics. Musculoskeletal models were developed at each testing timepoint (baseline or 12-months after implantation) and used to calculate joint kinematics, internal joint moments, and joint reaction forces (JRFs). Analyses were performed during three stance periods on each limb. The between-limb normalized symmetry index (NSI) was calculated for joint moments and JRF impulses. Discrete (range of motion (ROM), impulse NSI) dependent variables were compared before and after implantation using paired t-tests with Bonferroni-Holm corrections while continuous (ensemble averages of kinematics, moments, JRFs) were compared using statistical parametric mapping (p < 0.05). When using a bone-anchored limb, frontal plane pelvic (residual: pre = 9.6 ± 3.3°, post = 6.3 ± 2.5°, p = 0.004; intact: pre = 10.2 ± 3.9°, post = 7.9 ± 2.6°, p = 0.006) and lumbar (residual: pre = 15.9 ± 7.0°, post = 10.6 ± 2.5°, p = 0.024, intact: pre = 17.1 ± 7.0°, post = 11.4 ± 2.8°, p = 0.014) ROM was reduced compared to socket prosthesis use. The intact limb hip extension moment impulse increased (pre = -11.0 ± 3.6 Nm*s/kg, post = -16.5 ± 4.4 Nm*s/kg, p = 0.005) and sagittal plane hip moment impulse symmetry improved (flexion: pre = 23.1 ± 16.0 %, post = -3.9 ± 19.5 %, p = 0.004, extension: pre = 29.2 ± 20.3 %, post = 8.7 ± 22.9 %, p = 0.049). Residual limb knee extension moment impulse decreased compared to baseline (pre = 15.7 ± 10.8 Nm*s/kg, post = 7.8 ± 3.9 Nm*s/kg, p = 0.030). These results indicate that bone-anchored limb implantation alters multi-joint biomechanics, which may impact LBP or OA risk factors in the TTA population longitudinally.

Gardening/yardwork in people with knee osteoarthritis is not associated with symptom or structural progression over 48months: data from the Osteoarthritis Initiative.

To evaluate the relationship of gardening/yardwork with symptomatic and structural progression in those with pre-existing radiographic knee osteoarthritis (OA) in the Osteoarthritis Initiative (OAI), an observational study designed to evaluate potential and known biomarkers and risk factors of knee OA. We conducted a cohort study nested within the OAI, including participants ≥ 50years old with radiographic OA in at least one knee at the time of OAI enrollment. A participant reported the level of gardening/yardwork activity in a self-administered survey. Logistic regression analyses were used to evaluate the association of gardening/yardwork on new frequent knee pain, Kellgren-Lawrence (KL) worsening, medial joint space narrowing (JSN) worsening, and improved frequent knee pain. Of 1808 knees (1203 participants), over 60% of knees had KL grade = 2, 65% had medial JSN, and slightly more than a third had frequent knee symptoms. Gardeners/yardworkers and non-gardners/yardworkers had similar "worsening" outcomes for new knee pain (29% vs. 29%), KL worsening (19% vs. 18%), and medial JSN (23% vs. 24%). The adjusted odds ratio (OR) for the "worsening" outcomes of new knee pain, KL worsening, and medial JSN worsening were 1.0 (0.7-1.3), 1.0 (0.8-1.3), and 1.1 (0.9-1.4), respectively. The gardeners/yardworkers had an adjusted OR of 1.2 (0.9-1.7) for improved knee pain compared with non-gardners/yardworkers. Gardening/yardwork is not associated with knee OA progression and should not be discouraged in those with knee OA. Key Points • Gardening/yardwork is not associated with knee OA symptomatic or structural progression. • Gardening/yardwork should not be discouraged in people with knee OA.

Nonoperative Treatment as an Option for Isolated Anterior Cruciate Ligament Injury: A Systematic Review and Meta-analysis.

An anterior cruciate ligament (ACL) tear is a risk factor for early osteoarthritis (OA) onset. Generally, ACL reconstruction (ACLR) is associated with better outcomes. However, there is a lack of evidence regarding the effect of operative versus nonoperative treatment for preventing premature knee OA in isolated ACL tears while achieving good functional outcomes. The purpose of the study was to compare the outcomes of ACLR to primarily nonoperative management of isolated ACL tears. It was hypothesized that the outcomes between treatment types would be similar. Systematic review; Level of evidence, 3. This systematic review was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (registration No. CRD42021285901) and was conducted according to the Cochrane Handbook guidelines. We systematically searched for randomized and nonrandomized studies that compared ACLR with nonoperative treatments in isolated ACL tears in 3 databases until October 25, 2021. The risk of bias and quality of evidence of the included studies was assessed in accordance with the Cochrane guidelines. The primary outcome was radiologic signs of OA, and the secondary outcomes were functional parameters. Using the common effects model, we calculated pooled mean differences (MDs) and odds ratios (ORs) with 95% CIs. Five studies-2 randomized controlled trials (RCTs) and 3 retrospective non-RCTs-were included. There was a moderate risk of bias in 2 studies and a serious risk of bias in 1 study. The quality of evidence was rated low because of the higher risk of bias and inconsistency. Nonoperatively treated knees showed a trend toward lower odds of developing radiological signs of OA (OR, 1.84 [95% CI, 0.90 to 3.75]); however, surgically reconstructed knees had significantly better stability (MD, -2.44 [95% CI, -3.21 to -1.66 ]) and a trend toward better but clinically not meaningful Lysholm scores (MD, 2.88 [95% CI, -1.09 to 6.85]). The qualitative synthesis showed that surgical reconstruction was protective against subsequent injuries but not superior when returning to previous activity levels or various functional tests. Findings indicated that there is no certain evidence that ACLR for an isolated ACL tear is superior to nonoperative treatment. Clinicians should consider nonoperative treatments with a well-designed rehabilitative program as a primary option. However, these findings must be interpreted with caution because of low study quality and high risk of bias.

Sex differences in osteoarthritis prevalence, pain perception, physical function and therapeutics

ObjectiveWomen have a higher prevalence of osteoarthritis (OA) and worse clinical courses than men. However, the underlying factors and therapeutic outcomes of these sex-specific differences are incompletely researched. This review examines the current state of knowledge regarding sex differences in OA prevalence, risk factors, pain severity, functional outcomes, and use and response to therapeutics. MethodsPubMed database was used with the title keyword combinations “{gender OR sex} AND osteoarthritis” plus additional manual search of the included papers for pertinent references, yielding 212 references. Additional references were added and 343 that were reviewed for appropriateness. ResultsGlobally, women account for 60% of people with osteoarthritis with a greater difference after age 40. The higher risk for women may be due to differences in joint anatomy, alignment, muscle strength, hormonal influences, obesity, and/or genetics. At the same radiographic severity, women have greater pain severity than men, which may be explained by biologically distinct pain pathways, differential activation of central pain pathways, differences in pain sensitivity, perception, reporting, and coping strategies. Women have greater limitations of physical function and performance than men independent of BMI, OA severity, injury history, amount of weekly exercise. Women also have greater use of analgesic medications than men but less use of arthroplasty and poorer prognosis after surgical interventions. ConclusionsThe recognition of sex differences in OA manifestations and management could guide tailoring of sex-specific treatment protocols, and analysis of sex as a biological variable in future research would enhance development of precision medicine.

Effects of Bariatric Surgery on Knee Articular Cartilage and Osteoarthritis Symptoms-A 12-Month Follow-Up Using T2 Relaxation Time and WOMAC Osteoarthritis Index.

Obesity is a significant risk factor for osteoarthritis (OA). The most effective treatment for morbid obesity is bariatric surgery. To study the effects of potential surgically induced weight loss on knee articular cartilage and OA symptoms of obese patients over a 12-month follow-up. Prospective longitudinal cohort study. 45 obese patients (38 female, BMI = 42.3 ± 6.5 kg/m2) who underwent gastric bypass (intervention group), and 46 age-matched conservative-care controls (37 female, BMI = 39.8 ± 4.6 kg/m2). Multiecho spin echo sequence at 3 T. Knee cartilage T2 measurements and WOMAC Indices were measured presurgery and after 12 months. The intervention group was split into successful (≥20% total weight loss (TWL)) and unsuccessful (<20% TWL) weight loss groups. T2 and WOMAC indices were also measured in controls at baseline and after 12 months. Changes among the three groups were analyzed. Analysis of variance (significance level 0.05). Twenty-six (58%) intervention patients achieved ≥20% TWL. The <20% TWL group demonstrated significantly more T2 reduction in the deep lateral femur over 12 months compared with the ≥20% TWL group (-3.83 ± 8.18 msec vs. 2.47 ± 6.54 msec, respectively), whereas no significant differences were observed on the medial femoral compartment (P = 0.385, P = 0.551, and P = 0.511 for bulk, superficial and deep regions, respectively). Changes in WOMAC indices over 12 months were significantly greater in the ≥20% TWL group compared with controls. In the <20% TWL group, pain significantly improved over 12 months compared with controls, while stiffness and function changes were not statistically significant (P = 0.063 and P = 0.051, respectively). Cartilage matrix, measured by T2, showed improvement on lateral femoral cartilage with <20% TWL compared with ≥20% TWL. Bariatric surgery provided significant improvements in knee symptoms with ≥20% TWL compared with conservative WL. This effect is also seen to some extent with <20% TWL compared with conservative WL. 2 TECHNICAL EFFICACY: Stage 4.

Phenome-wide causal associations between osteoarthritis and other complex traits through the latent causal variable analysis

BackgroundIndividuals with osteoarthritis present with comorbidities, and the potential causal associations remain incompletely elucidated. The present study undertook a large-scale investigation about the causality between osteoarthritis and variable traits, using the summary-level data of genome-wide association studies (GWAS).MethodsThe present study included the summary-level GWS data of knee osteoarthritis, hip osteoarthritis, hip or knee osteoarthritis, hand osteoarthritis, and other 1355 traits. Genetic correlation analysis was conducted between osteoarthritis and other traits through cross-trait bivariate linkage disequilibrium score regression. Subsequently, latent causal variable analysis was performed to explore the causal association when there was a significant genetic correlation. Genetic correlation and latent causal variable analysis were conducted on the Complex Traits Genomics Virtual Lab platform (https://vl.genoma.io/).ResultsWe found 133 unique phenotypes showing causal relationships with osteoarthritis. Our results confirmed several well-established risk factors of osteoarthritis, such as obesity, weight, BMI, and meniscus derangement. Additionally, our findings suggested putative causal links between osteoarthritis and multiple factors. Socioeconomic determinants such as occupational exposure to dust and diesel exhaust, extended work hours exceeding 40 per week, and unemployment status were implicated. Furthermore, our analysis revealed causal associations with cardiovascular and metabolic disorders, including heart failure, deep venous thrombosis, type 2 diabetes mellitus, and elevated cholesterol levels. Soft tissue and musculoskeletal disorders, such as hallux valgus, internal derangement of the knee, and spondylitis, were also identified to be causally related to osteoarthritis. The study also identified the putative causal associations of osteoarthritis with digestive and respiratory diseases, such as Barrett’s esophagus, esophagitis, and asthma, as well as psychiatric conditions including panic attacks and manic or hyperactive episodes. Additionally, we observed osteoarthritis causally related to pharmacological treatments, such as the use of antihypertensive medications, anti-asthmatic drugs, and antidepressants.ConclusionOur study uncovered a wide range of traits causally associated with osteoarthritis. Further studies are needed to validate and illustrate the detailed mechanism of those causal associations.

Low-intensity pulsed ultrasound delays the progression of osteoarthritis by regulating the YAP-RIPK1-NF-κB axis and influencing autophagy.

Osteoarthritis (OA) is a degenerative disease characterized by chronic inflammation of the joint. As the disease progresses, patients will gradually develop symptoms such as pain, physical limitations and even disability. The risk factors for OA include genetics, gender, trauma, obesity, and age. Unfortunately, due to limited understanding of its pathological mechanism, there are currently no effective drugs or treatments to suspend the progression of osteoarthritis. In recent years, some studies found that low-intensity pulsed ultrasound (LIPUS) may have a positive effect on osteoarthritis. Nonetheless, the exact mechanism by which LIPUS affects osteoarthritis remains unknown. It is valuable to explore the specific mechanism of LIPUS in the treatment of OA. In this study, we validated the potential therapeutic effect of LIPUS on osteoarthritis by regulating the YAP-RIPK1-NF-κB axis at both cellular and animal levels. To verify the effect of YAP on OA, the expression of YAP was knocked down or overexpressed by siRNA and plasmid in chondrocytes and adeno-associated virus was injected into the knee joint of rats. The effect of LIPUS was investigated in inflammation chondrocytes induced by IL-1β and in the post-traumatic OA model. In this study, we observed that YAP plays an important role in the development of osteoarthritis and knocking down of YAP significantly inhibited the inflammation and alleviated cartilage degeneration. We also demonstrated that the expression of YAP was increased in osteoarthritis chondrocytes and YAP could interact with RIPK1, thereby regulating the NF-κB signal pathway and influencing inflammation. Moreover, we also discovered that LIPUS decreased the expression of YAP by restoring the impaired autophagy capacity and inhibiting the binding between YAP and RIPK1, thereby delaying the progression of osteoarthritis. Animal experiment showed that LIPUS could inhibit cartilage degeneration and alleviate the progression of OA. These results showed that LIPUS is effective in inhibiting inflammation and cartilage degeneration and alleviate the progression of OA. As a result, our results provide new insight of mechanism by which LIPUS delays the development of osteoarthritis, offering a novel therapeutic regimen for osteoarthritis.

Chondroitin Sulfate for Osteoarthritis – Is There a Risk for Cancer: an Analysis of Osteoarthritis Initiative Data

The aim of this study was to evaluate the association between chondroitin   sulfate (CS) use and incidence of self-reported cancer during 6-year follow up in the     publicly available Osteoarthritis Initiative (OAI) cohort participants.&#x0D; Materials and Methods: The current study included analysis of 6-year longitudinal data obtained from the OAI progression (n= 1390) and incidence (n = 3284) subcohorts that are publicly available at https://nda.nih.gov/oai/. The inclusion criteria for OAI were the following: age between 45 and 79 years for both subcohorts, symptomatic tibiofemoral knee osteoarthritis (OA) for the progression subcohort, and the presence of established or putative risk factors for incident knee OA for the incidence subcohort. The OAI participants were recruited and enrolled between February 2004 and May 2006 at four recruitment centres in the United States. This study received ethical approval from each recruitment centre. All participants provided written informed consent. To reduce the risk of bias, only participants who did not take CS at baseline were included in the analysis (a “new-user” design).&#x0D; Results: 570 (18%) new users of CS and 2597 (82%) CS non-users were compared. In the CS user group, 294 (51.6%) participants received CS for more than one year, 291 (33.5%) for more than 2 years, 123 (21.6%) for more than 3 years, and 60 (10.5%) for more than 4 years. None of the participants received CS for more than 5 years. CS users and non-users were of the same age, had similar male/female ratio, and similar body mass index. In the non-user group, there were more African-American participants and there were more current smokers. 160 (6.2%) and 37 (6.5%) cases of incident self-reported cancer in the non-users and user groups were identified. There was no association between the use of CS and incident self-reported cancer in the non-adjusted analyses. The adjustments for age, race and smoking status did not change the results.&#x0D; Conclusion: The results of the current study did not show an association between CS use and self-reported cancers. Considering the complex function of CS in the development and progression of malignant tumors, there is a need for further epidemiological studies evaluating CS effects on specific types of cancers and in different genetic backgrounds.

Cigarette smoke extract exacerbates progression of osteoarthritic-like changes in cartilage explant cultures.

Established risk factors for osteoarthritis (OA) include obesity, joint injury, age, race, and genetics. However, the relationship between cigarette smoking and OA has yet to be established. In the present study, we have employed the use of cigarette smoke extract (CSE), the water-soluble vapor phase of cigarette smoke, with porcine cartilage explants to investigate the effects of cigarette smoking on cartilage catabolism at the tissue level. Articular cartilage explants were first exposed to 2.5%, 5%, and 10% CSE to assess its effects on cartilage homeostasis. Following, the effects of CSE on OA-like inflammation was observed by culturing explants with a combined treatment of IL-1β and TNF-α and 10% CSE (CSE + OA). Cartilage explants were assessed for changes in viability, biochemical composition, extracellular matrix (ECM) integrity, and equilibrium mechanical properties (aggregate modulus and hydraulic permeability). CSE alone leads to both a time- and dose-dependent decrease in chondrocyte viability but does not significantly affect sGAG content, percent sGAG loss, or the ECM integrity of cartilage explants. When IL-1β and TNF-α were combined with 10% CSE, this led to a synergistic effect with more significant losses in viability, significantly more sGAG loss, and significantly higher production of ROS than OA-like inflammation only. Cartilage explant equilibrium mechanical properties were unaffected. Within the timeframe of this study, CSE alone does not cause OA but when combined with OA-like inflammation leads to worsened articular cartilage degeneration as measured by chondrocyte viability, sGAG loss, proteoglycan staining, and ROS production.

Dissecting the causal relationship between neuroticism and osteoarthritis: a univariable and multivariable Mendelian randomization study.

Mental health has been found to be associated with risk of osteoarthritis (OA), but the causal relationship was not fully clarified. Two-sample Mendelian randomization (MR) study was conducted to investigate the causal relationship between neuroticism (n = 329,821) and the two most frequently affected parts of osteoarthritis (OA) (knee OA: case/control =24,955/378,169; hip OA: case/control = 15,704/378,169) using large scale summary genome-wide association study (GWAS) data. Inverse variance weighted (IVW), weighted median, and MR-Egger were used to estimate the causal effects. Multiple sensitivity analyses were conducted to examine the robustness of the causal estimates. Multivariable MR analysis was used to estimate the direct effects of neuroticism on OA after accounting for the other OA risk factors. Two-step MR approach was employed to explore the potential mediators of the causal relationship. Univariable MR analysis indicated that 1-SD increase in genetically predicted neuroticism score was associated with an increased risk of knee OA (IVW: OR, 1.17; 95% CI, 1.087-1.26; p = 2.72E-05) but not with hip OA. The causal effects remained significant after accounting for the effects of BMI, alcohol drinking, and vigorous physical activity but were attenuated with adjustment of smoking. Further mediation analysis revealed that smoking initiation mediated a significant proportion of the causal effects of neuroticism on knee OA (proportion of mediation effects in total effects: 22.3%; 95% CI, 5.9%-38.6%; p = 7.60E-03). Neuroticism has significant causal effects on knee OA risk. Smoking might partly mediate the causal relationship. Further studies were warranted to explore the underlying mechanisms and potential use of neuroticism management for OA treatment.

Predisposal of Interferon Regulatory Factor 1 Deficiency to Accumulate DNA Damage and Promote Osteoarthritis Development in Cartilage.

Interferon regulatory factor 1 (IRF1) is a transcriptional regulator conventionally associated with immunomodulation. Recent molecular analyses mapping DNA binding sites of IRF1 have suggested its potential function in DNA repair. However, the physiologic significance of this noncanonical function remains unexplored. Here, we investigated the role of IRF1 in osteoarthritis (OA), a condition marked by senescence and chronic joint inflammation. OA progression was examined in wild-type and Irf1-/- mice using histologic assessments and microcomputed tomography analysis of whole-joint OA manifestations and behavioral assessments of joint pain. An integrated analysis of assay for transposase-accessible chromatin with sequencing and whole transcriptome data was conducted for the functional assessment of IRF1 in chondrocytes. The role of IRF1 in DNA repair and senescence was investigated by assaying γ-H2AX foci and senescence-associated beta-galactosidase activity. Our genome-wide investigation of IRF1 footprinting in chondrocytes revealed its primary occupancies in the promoters of DNA repair genes without noticeable footprint patterns in those of interferon-responsive genes. Chondrocytes lacking IRF1 accumulated irreversible DNA damage under oxidative stress, facilitating their entry into cellular senescence. IRF1 was down-regulated in the cartilage of human and mouse OA. Although IRF1 overexpression did not elicit an inflammatory response in joints or affect OA development, genetic deletion of Irf1 caused enhanced chondrocyte senescence and exacerbated post-traumatic OA in mice. IRF1 offers DNA damage surveillance in chondrocytes, protecting them from oxidative stress associated with OA risk factors. Our study provides a crucial and cautionary perspective that compromising IRF1 activity renders chondrocytes vulnerable to cellular senescence and promotes OA development.