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The role of Interleukin-40 (IL-40) in rheumatoid arthritis (RA) is not well understood, and this study was designed to explore serum IL-40 levels in RA patients to assess its potential as a disease biomarker. In this research, serum IL-40 levels were determined using enzyme-linked immunosorbent assay in 116 patients with RA, 40 with osteoarthritis (OA), 29 with systemic lupus erythematosus (SLE), and 66 healthy controls (HCs). Paired serum samples were collected from 86 of the 116 patients treated during follow-up visits at week 12. Group comparison analysis showed that serum IL-40 levels were significantly higher in patients with RA than in HCs, and the areas under the curve for IL-40 were 0.688, 0.865, and 0.870 for distinguishing patients with RA from HCs and those with OA and SLE, respectively. Furthermore, in RA, serum IL-40 levels were lower in patients with comorbidities of cardiovascular diseases or OA. Correlation analyses revealed that serum IL-40 levels were positively associated with RA-related autoantibodies and coagulation-related indicators, whereas no correlation was observed with disease activity-associated factors. When comparing paired samples, treatment with TNF inhibitors (TNFi) significantly reduced serum IL-40 levels, emphasizing its potential as a treatment guide., Competing Interests: Declaration. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: To determine whether obesity and markers of lipid metabolism are associated with radiological hand osteoarthritis (OA) in the Halland County Osteoarthritis (HALLOA) cohort., Methods: In this cross-sectional study, we included 231 participants aged 30-65 from the HALLOA cohort, which began in 2017 and is ongoing. Hand OA was defined as ≥ 2 joint groups (distal interphalangeal, proximal interphalangeal, and carpometacarpal I) with Kellgren-Lawrence grade ≥ 2. The severity of hand OA was classified in terms of the number of affected joint groups (moderate hand OA 2-4 joint groups, severe hand OA 5-6 joint groups). Metabolic profile, including body mass index (BMI), bioimpedance, waist circumference, blood pressure, serum leptin, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides, were obtained. Multicollinearity was assessed with Pearson's correlation and associations with logistic regression analyses adjusting for age, HDL-cholesterol, and central obesity., Results: Two-thirds of the participants were women, and 91 (39%) had hand OA. We found a relationship between LDL-cholesterol and prevalent hand OA in women with an odds ratio of 1.7 (95% CI 1.1-2.6) and an association between LDL-cholesterol and severity of hand OA in women; odds ratio for no hand OA vs. moderate hand OA was 1.6 (95% CI 1.0-2.4) and for no hand OA vs. severe hand OA 2.5 (95% CI 1.2-4.9). There were no significant relationships between hand OA and obesity or serum leptin levels., Conclusion: Circulating LDL-cholesterol levels were associated with the prevalence and severity of hand OA in women but not men., Trial Registration: ClinicalTrials. Gov (NCT04928170), Date of registration: 2017-12-20., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved, in accordance with the Declaration of Helsinki, by the Regional Ethical Review Board, Faculty of Medicine, University of Lund, Sweden (2016/229, 2017/253, and 2020–03866). All individuals gave their informed consent to participate in the study and to publish results on a group level. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Osteoarthritis (OA) is a degenerative joint disease prevalent in the elderly. Currently, the relationship between the senescence inhibitor Klotho and OA remains unclear. This study investigated the relationship between serum soluble Klotho (S-Klotho) and OA., Methods: This cross-sectional study was based on the 2007-2016 National Health and Nutrition Examination Survey (NHANES). Three multifactorial logistic regression models were constructed to assess the association between serum Klotho and OA. Restricted cubic spline (RCS) curves were further used to assess whether there was a nonlinear relationship between serum Klotho and OA. Finally, stratified analyses and interaction tests were used to evaluate the association's stability. To further investigate the relationship between serum Klotho and OA, we recruited 107 patients for analysis at the First Affiliated Hospital of Guangxi Medical University., Results: The final 8,918 participants included in this study comprised 50.55% females and 49.45% males, with 18.10% of participants suffering from OA and a mean S-Klotho level of 846.41 (5.61) pg/ml. All three logistic regression models observed a negative association between continuous S-Klotho and OA risk. When S-Klotho was categorized into tertiles, the fully adjusted model showed that participants in the third tertile had a 17% lower risk of OA than those in the first tertile (OR = 0.83, 95% CI: 0.70, 0.99, P = 0.035). The RCS curves showed a linear negative association between S-Klotho and the incidence of OA (P for overall = 0.025; P for non-linearity = 0.667). Further subgroup analyses and interaction tests suggested that the negative association between S-Klotho and OA remained stable in different conditions. Research conducted in China has shown that the negative correlation between serum Klotho levels and the prevalence of OA remains evident among Chinese individuals (OR: 0.77, 95% CI: 0.66, 0.90, P<0.001)., Conclusion: Our study suggests that elevated levels of the senescence inhibitor S-Klotho may be a potential protective factor for OA, which may provide new insights into the diagnosis and treatment of OA., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Qiu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: This study aimed to provide insight into the effect of genetically predicted linoleic acid (LA) levels on osteoarthritis (OA)., Methods: The LA dataset was obtained from the UK Biobank (UKBB) consortium and contained 114,999 samples. The OA discovery dataset was derived from MRC-IEU consortium and included 38,472 cases and 424,461 controls. The OA validation set was derived from a summary-level genome-wide association study (GWAS) and included 39,427 cases and 378,169 controls. Genetic variants strongly associated with LA (p < 5 × 10 - 8 ) were extracted as instrumental variables (IVs). The inverse variance weighted (IVW) approach was adopted as the primary analysis method in this study. In addition, multiple sensitivity analysis methods were used to assess the reliability of our results., Results: The IVW approach showed that circulating LA levels were negatively associated with OA risk in the discovery set (odds ratio (OR) = 0.993, 95% confidence interval (95% CI): 0.988-0.998, p = 0.011). A consistent result was obtained in the validation set (OR = 0.904, 95%CI: 0.845-0.967, p = 0.003). These results were validated by sensitivity analysis., Conclusion: This study provides new evidence for the causal relationship between LA and OA, which provides new insights for the treatment of OA., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Clinical trial number Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Previous studies have demonstrated a relationship between prevalence of Osteoarthritis (OA) and insulin resistance (IR). The correlation between IR surrogates indices and gold standard tool for IR evaluation (Hyperinsulinemic-euglycemic clamp (HIEC)) have been well demonstrated. However, few studies evaluated the relationship between IR surrogates and OA. The aim of this study is to investigate the potential associations between different IR surrogates (the homeostatic model assessment of insulin resistance (HOMA-IR) index, the triglyceride glucose (TyG) index, the triglyceride glucose with body mass (TyG-BMI) index, the triglyceride glucose with waist circumference (TyG-WC) index, and the triglyceride glucose with the ratio of waist circumference divided by height (TyG-WtHR) index) and OA., Methods: This study used data from the National Health and Nutrition Examination Survey (NHANES). Multivariate logistic regression analysis was used to assess the associations of different IR surrogates with OA., Results: After adjusting for covariates, TyG-BMI index (OR = 1.006, 95% CI [1.004, 1.007], P < 0.0001), TyG-WC index (OR = 1.002, 95% CI [1.002, 1.003], P < 0.0001) and TyG-WtHR index (OR = 1.425, 95%CI [1.292,1.572], P < 0.0001) still showed robust positive correlation with IR. The risk of OA in the fourth quartile of the TyG-BMI index, TyG-WC index, and TyG-WtHR index are 2.634-fold, 2.651-fold, and 2.433-fold higher than that in the first quartile, respectively., Conclusions: Compared to the HOMA-IR index and the TyG index, the association between the TyG-BMI, TyG-WC, and TyG-WtHR indices and OA is closer and more stable. The TyG-WtHR index has the highest accuracy in predicting OA, followed by the TyG-WC and TyG-BMI index., Competing Interests: Declarations Ethics approval and consent to participate In accordance with the Declaration of Helsinki, the NHANES protocol was approved by the NCHS Research Ethics Review Board, and informed consent was obtained from all participants. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Sarcopenic obesity (SO) and osteoarthritis (OA) are highly prevalent musculoskeletal conditions that significantly impair health-related quality of life., Aim: This study investigated the association between SO and OA, and explored the potential mediating role of insulin resistance in this relationship. We utilized data from the National Health and Nutrition Examination Survey (NHANES) 1999-2018., Methods: This cross-sectional analysis employs NHANES data collected from 1999 to 2018, including participants aged 18 years and older. SO was assessed using dual-energy X-ray absorptiometry (DXA) measurements. Insulin resistance was estimated using the triglyceride-glucose (TyG) index. OA status was based on self-reported physician diagnosis. Statistical analyses included weighted logistic regression, restricted cubic spline (RCS) interaction analysis, mediation analysis using structural equation modeling (SEM), and receiver operating characteristic (ROC) curve analysis. Subgroup analyses were conducted based on age, sex, and diabetes status., Results: The sarcopenic obese group demonstrated the highest prevalence of OA (23.4 %), hypertension (47.8 %), and diabetes (12.0 %). Additionally, they exhibited elevated levels of triglycerides, cholesterol, glucose, blood urea nitrogen (BUN), creatinine, and uric acid. Logistic regression revealed significant positive associations between sarcopenic obesity, the TyG index, and OA risk. RCS analysis identified significant non-linear relationships and interactions of the TyG index with age, sex, and diabetes status on OA risk. Mediation analysis indicated that the TyG index mediated approximately 4.9 % of the effect of sarcopenic obesity on OA risk. ROC curve analysis demonstrated moderate diagnostic accuracy for the TyG index (AUC = 0.65), which improved when incorporated into the multivariate model (AUC = 0.78). Subgroup analyses confirmed significant associations between the TyG index and sarcopenic obesity with OA risk across different age, sex, and diabetes status categories., Conclusion: Our findings suggest a significant correlation between insulin resistance, as measured by the TyG index, and elevated OA risk in individuals with sarcopenic obesity. Targeting insulin resistance through future research may be a promising avenue to lower OA risk in this population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To identify circulating micro-RNAs differentially expressed in patients with erosive hand osteoarthritis (HOA) compared to patients with non-erosive HOA and patients without HOA., Methods: In the screening phase, 768 well-characterized micro-RNAs using Taqman low-density array cards were measured in 30 sera from 10 patients with erosive HOA, 10 patients with non-erosive HOA, and 10 controls without HOA, matched for age and body mass index (BMI). In a second step, we validated the micro-RNAs identified at the screening phase (adjusted p value < 0.05 after false discovery rate correction using Benjamini-Hochberg method and literature review) in larger samples (60 patients with erosive HOA and 60 patients without HOA matched for age and BMI)., Results: In the screening phase, we identified 21 down-regulated and 4 up-regulated micro-RNAs of interest between erosive HOA and control groups. Among these, 9 micro-RNAs (miR-373-3p, miR-558, miR-607, miR-653-5p, miR-137 and miR448 were down-regulated, and miR-142-3p, miR-144-3p and miR-34a-5p were up-regulated) were previously described in chondrocytes homeostasis or OA. We found only one significantly down-regulated micro-RNA between erosive and non-erosive HOA. In the validation phase, we showed replication of a single micro-RNA the significant downregulation of miR-196-5p, that had been previously identified in the screening phase among patients with erosive HOA compared to those without HOA. After reviewing the literature and the miRNA-gene interaction prediction model, we found that this microRNA could interact with bone homeostasis and HOXC8, which could explain its role in osteoarthritis., Conclusions: We found that miR-196-5p was down-regulated in patients with erosive HOA and some of its targets could explain a role in OA., (Copyright © 2024 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

With the aging of the global population and the increase in the number of people with conditions such as obesity, the incidence of osteoarthritis (OA) is increasing annually. Clinical studies have shown that excessive accumulation of iron in joints is associated with age-related OA. However, there have been no reports on the relationship between iron metabolism and osteoarthritis. A STROBE-compliant cross-sectional observational study, was carried out and analyzed from the National Health and Nutrition Examination Survey from 2001 to 2020, including data on serum iron, transferrin saturation, serum ferritin, total iron-binding capacity, and transferrin receptors, as well as data on osteoarthritis. This cross-sectional study was conducted to explore the relationship between serum iron levels, osteoarthritis, and related metabolic factors. By adjusting the model and using quantile logistic regression models, the interaction between human body iron content and the aforementioned variables was analyzed. A total of 56,323 participants over 5 cycles were assessed for iron levels. After adjusting the model for age, sex, race, education level, marital status, total energy intake, physical activity, drinking, BMI, smoking, hypertension, and diabetes, we found that in different quantile regression results, serum iron was associated with OA, Q4: OR = 1.231 (95%CI: 1.009-1.501, P < .05). Ferritin is associated with OA, Q2: OR = 1.309 (95%CI: 1.012-1.692, P < .05); Q3: OR = 1.424 (95%CI: 1.129-1.797, P < .01); Q4: OR = 1.280 (95%CI: 1.013-1.616, P < .05). This cross-sectional study found that serum iron and transferrin saturation levels were positively correlated with OA incidence, suggesting that iron overload is a risk factor for OA. Large-sample prospective cohort studies are needed to confirm the correlation between iron overload and OA., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Osteoarthritis (OA) is a chronic, progressive, degenerative joint disease characterized by joint pain, stiffness, and limited movement. It presents significant intra- and inter-individual variability-in particular, between genders. Recent research has increasingly focused on the role of adipokines-especially leptin, adiponectin, and resistin-in the development of OA. Adipokines, peptide hormones primarily secreted by adipose tissue, are involved in crucial physiological processes related to metabolism and immunity. They can also impact bone and cartilage turnover by interacting with joint cells such as osteoblasts, osteoclasts, chondrocytes, and mesenchymal stem cells, thereby linking inflammation with bone cartilage homeostasis. This review aims to elucidate the structure and functions of various adipokines, their serum and synovial levels, and their association with clinical presentation and radiographic progression in OA patients, with a focus on differences between sexes. A narrative literature review was conducted using three databases specifically analyzing sex differences. OA patients generally show elevated serum and synovial levels of leptin, chemerin, and visfatin, as well as high plasma levels of resistin and visfatin. In contrast, synovial levels of adiponectin and omentin are reduced in OA patients compared to healthy individuals, with an inverse relationship to disease severity, suggesting a potential protective role. Resistin and leptin were positively correlated with pain severity and radiographic progression, while adiponectin's role in OA remains controversial. Regarding sex differences, male OA patients exhibited higher serum levels of leptin, chemerin, and omentin compared to healthy controls, with a positive correlation to the BMI and estrogen levels, potentially explaining the sexual dimorphism observed in this condition. Studies on visfatin and lipocalin did not reveal significant differences in synovial or serum levels between the sexes. The role of resistin remains controversial. Adipokines influence the joint microenvironment and contribute to the progression of osteoarthritis (OA). However, the precise biological mechanisms are not yet fully understood due to the complex interactions between the metabolic, mechanical, and immune systems. Further research is needed to clarify their roles in OA and to identify targeted therapies for managing this degenerative disease.

Background: The complete circulating long non-coding RNAs (lncRNAs) signature of rheumatoid arthritis (RA) and osteoarthritis (OA) is still uncovered. The lncRNA integrin subunit beta 2 (ITGB2)-anti-sense RNA 1 (ITGB2-AS1) affects ITGB2 expression; however, there is a gap in knowledge regarding its expression and clinical usefulness in RA and OA. This study investigated the potential of serum ITGB2-AS1 as a novel diagnostic biomarker and its correlation with ITGB2 expression and its ligand intercellular adhesion molecule-1 (ICAM-1), disease activity, and severity in RA and primary knee OA patients., Subjects: Forty-three RA patients, 35 knee OA patients, and 22 healthy volunteers were included., Results: Compared with healthy controls, serum ITGB2-AS1 expression was upregulated in RA patients but wasn't significantly altered in knee OA patients, whereas serum ICAM-1 protein levels were elevated in both diseases. ITGB2-AS1 showed discriminative potential for RA versus controls (AUC = 0.772), while ICAM-1 displayed diagnostic potential for both RA and knee OA versus controls (AUC = 0.804, 0.914, respectively) in receiver-operating characteristic analysis. In the multivariate analysis, serum ITGB2-AS1 and ICAM-1 were associated with the risk of developing RA, while only ICAM-1 was associated with the risk of developing knee OA. A panel combining ITGB2-AS1 and ICAM-1 showed profound diagnostic power for RA (AUC = 0.9, sensitivity = 86.05%, and specificity = 91.67%). Interestingly, serum ITGB2-AS1 positively correlated with disease activity (DAS28) in RA patients and with ITGB2 mRNA expression in both diseases, while ICAM-1 positively correlated with ITGB2 expression in knee OA patients., Conclusion: Our study portrays serum ITGB2-AS1 as a novel potential diagnostic biomarker of RA that correlates with disease activity. A predictive panel combining ITGB2-AS1 and ICAM-1 could have clinical utility in RA diagnosis. We also spotlight the association of ICAM-1 with knee OA diagnosis. The correlation of serum ITGB2-AS1 with ITGB2 expression in both diseases may be insightful for further mechanistic studies., (© 2024. The Author(s).)

Background: Obesity is associated with an increased risk for different chronic diseases such as osteoarthritis (OA) or rheumatoid arthritis (RA). In fact, adipose tissue is now recognized as an endocrine organ able to secrete a wide variety of factors called adipokines, which have been demonstrated to participate in the pathophysiology of RA by regulating inflammation and immunity. LCN2 is one of these adipose tissue-derived factors. However, scarce information is available about the levels of this adipokine in different rheumatic diseases. Therefore, we aimed to analyze LCN2 serum levels in healthy, OA, and RA patients under different treatments., Methods: Serum levels of LCN2, among other proinflammatory and chemotactic factors, have been measured by ELISA or Multiplex in the following four groups of individuals: healthy, OA, and RA patients treated with conventional treatment or adalimumab., Results: We found increased serum levels of LCN2 in OA and RA patients. Interestingly, LCN2 serum levels show a similar pattern to that observed for different proinflammatory and chemotactic factors, being increased in RA conventional treated patients in comparison to RA patients treated with adalimumab. Also, RA patients under conventional treatment revealed a positive and significant correlation between LCN2 and CCL2, CCL3, IL-8, IL-1 β , IL-6, and CRP. In patients with RA treated with adalimumab, only IL-6 and CRP correlated significantly with LCN2., Conclusions: Our results clearly suggest that LCN2 is modulated and associated with inflammation in rheumatic diseases. Therefore, the serum levels of this adipokine might be used as an additional biomarker of the inflammatory/disease activity., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2024 Javier Conde-Aranda et al.)

Previous studies on the relationship between vitamin D, sleep quality, and osteoarthritis (OA) have been controversial and the aim of this study is to analyze the association. In this study, relevant data from 2 survey cycles (2009-2010 with 2011-2012) are downloaded from the CDC's NHANES project to analyze the relationship between vitamin D, sleep quality, and osteoarthritis, as well as other related risk factors. The analysis of statistics in this study is performed using t-tests and chi-square tests, modeling is performed using logistic regression based on NHANES weights, and other risk factors are analyzed using forest plots. In association models between serum vitamin D, sleep quality, and OA is statistically significant during the stepwise inclusion of covariates. In model 1, Q3 (OR = 1.83; 95% CI: 1.05, 3.23) and Q4 (OR = 2.22; 95% CI: 1.27, 3.94) are significant. Neither model 2 nor model 3 is statistically significant and P for trend is more than .05 in all 3 models. After the inclusion of all covariates, forest plot showed that sleep deprivation (OR = 1.64; 95% CI: 1.05, 2.56), advanced age (OR = 1.03; 95% CI: 1.01, 1.04), female (OR = 1.79; 95% CI: 1.14, 2.85), overweight (25 ≤ BMI < 30) (OR = 1.92; 95% CI: 1.05, 3.61), and obesity (≥30) (OR = 2.06; 95% CI: 1.11, 3.93) are risk factors for OA. This study is based on a larger sample and a stepwise logistic regression of multiple covariates. We concluded that vitamin D may not influence OA. However other risk factors for OA are confirmed, including advanced age, female and high BMI, especially bad sleep quality., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Metformin (MTF) shows promise in protecting against physical decline in osteoarthritis (OA), but how it works remains unclear. We studied MTF's effects on gut permeability and its link to physical performance in OA patients., Methods: We studied four groups: control (n = 72), OA non-diabetic (n = 58), OA diabetic on MTF (n = 55), and OA diabetic on other anti-diabetics (n = 57). We measured zonulin levels, as intestinal permeability marker, hand-grip strength (HGS), Oxford knee scoring (OKS) to determine OA severity, and short performance physical battery (SPPB) to determine physical functions., Results: Patients suffering from OA showed a reduction in HGS and SPPB scores with raised plasma zonulin than controls, irrespective of disease severity. MTF decreased plasma zonulin levels and improved OKS, gait speed, HGS, and SPPB scores in OA patients. However, OA patients taking other anti-diabetic medications demonstrated higher levels of plasma zonulin, reduced HGS, and SPPB scores. Furthermore, a robust correlation of plasma zonulin and HGS, OKS, gait speed, and SPPB scores in OA patients on MTF was observed. Moreover, we found reduced oxidative stress and inflammation associated with these alterations in OA patients treated with MTF., Conclusion: MTF improves HGS and physical performance by lowering zonulin levels, preserving gut permeability in OA patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Malondialdehyde-acetaldehyde (MAA) adducts lead to generation of anti-MAA autoantibodies and have been independently identified in inflamed periodontal and rheumatoid arthritis (RA) tissues. This study evaluates serum samples from RA cases and osteoarthritis (OA) controls to quantify associations between periodontal clinical measures, alveolar bone loss (ABL), and anti-Porphyromonas gingivalis, anti-Prevotella intermedia, and anti-Fusobacterium nucleatum antibody concentrations with anti-MAA antibody concentrations., Methods: Participants (n = 284 RA cases, n = 330 OA controls) underwent periodontal clinical assessments and ABL measurements. Serum immunoglobulin (Ig) A, IgG, and IgM anti-MAA and serum IgG antibacterial antibody concentrations were quantified by enzyme-linked immunosorbent assay (ELISA). Analyses utilized simple linear regression and multivariable adjusted models., Results: No significant associations of periodontal clinical measures with serum anti-MAA were found. Moderate (p = 0.038 and p = 0.036, respectively) and high ABL (p = 0.012 and p = 0.014, respectively) in RA cases (but not in OA) were positively associated with IgG and IgM anti-MAA. Anti-P. gingivalis and anti-P. intermedia antibody concentrations were positively associated with IgA (p = 0.001 for both), IgG (p = 0.007 and p = 0.034, respectively), and IgM anti-MAA antibody concentrations (p < 0.001 and p = 0.020, respectively), while anti-F. nucleatum was positively associated with IgG anti-MAA (p = 0.042), findings that were similar across groups., Conclusions: A positive association was demonstrated between ABL and serum IgG and IgM anti-MAA antibody concentrations that was unique to RA and not observed in OA. Serum anti-P. gingivalis, anti-P. intermedia, and anti-F. nucleatum antibody concentrations displayed significant associations with anti-MAA antibody in both groups. These findings suggest MAA may play a role in the interrelationship between the periodontium and RA., (© 2024 The Authors. Journal of Periodontology published by Wiley Periodicals LLC on behalf of American Academy of Periodontology.)

Background: According to reports, iron status has been associated with the risk of bone and joint-related diseases. However, the exact role of iron status in the development of these conditions remains uncertain., Method: We obtained genetic data on iron status, specifically serum iron, ferritin, transferrin saturation (TSAT), and transferrin, as well as data on five common bone and joint-related diseases (osteoarthritis, osteoporosis, rheumatoid arthritis [RA], ankylosing spondylitis [AS], and gout) from independent genome-wide association studies involving individuals of European ancestry. Our primary approach for causal estimation utilized the inverse variance weighted (IVW) method. To ensure the reliability of our findings, we applied complementary sensitivity analysis and conducted reverse causal analysis., Result: Using the IVW method, we revealed a positive causal relationship between ferritin levels and the risk of osteoarthritis (OR [95% CI], 1.0114 [1.0021-1.0207]). Besides, we identified a protective causal relationship between serum iron levels and TSAT levels in the risk of RA (OR [95% CI] values of serum iron and TSAT were 0.9987 [0.9973-0.9999] and 0.9977 [0.9966-0.9987], respectively). Furthermore, we found a positive causal relationship between serum iron levels and the risk of AS (OR [95% CI], 1.0015 [1.0005-1.0026]). Regarding gout, both serum iron and TSAT showed a positive causal relationship (OR [95% CI] values of 1.3357 [1.0915-1.6345] and 1.2316 [1.0666-1.4221] for serum iron and TSAT, respectively), while transferrin exhibited a protective causal relationship (OR [95% CI], 0.8563 [0.7802-0.9399]). Additionally, our reverse causal analysis revealed a negative correlation between RA and ferritin and TSAT levels (OR [95% CI] values of serum iron and TSAT were 0.0407 [0.0034-0.4814] and 0.0049 [0.0002-0.1454], respectively), along with a positive correlation with transferrin (OR [95% CI], 853.7592 [20.7108-35194.4325]). To ensure the validity of our findings, we replicated the results through sensitivity analysis during the validation process., Conclusion: Our study demonstrated a significant correlation between iron status and bone and joint-related diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Qiu, Yang, Wu, Xie, Zhang, Li, Li, Gao and Zhang.)

Background: Osteoarthritis (OA) is a degenerative osteoarticular disease, involving genetic predisposition. How the risk variants confer the risk of OA through their effects on proteins remains largely unknown. Therefore, we aimed to discover new and effective drug targets for OA and its subtypes., Methods: A proteome-wide association study (PWAS) was performed based on OA and its subtypes genome-wide association studies (GWAS) summary datasets and the protein quantitative trait loci (pQTL) data. Subsequently, Mendelian randomization (MR) and colocalization analysis was conducted to estimate the associations between protein and OA risk. The replication analysis was performed in an independent dataset of human plasma pQTL data., Results: The abundance of seven proteins was causally related to OA, two proteins to knee OA and six proteins to hip OA, respectively. We replicated 2 of these proteins using an independent pQTL dataset. With the further support of colocalization, and higher ECM1 level was causally associated with a higher risk of OA and hip OA. Higher PCSK1 level was causally associated with a lower risk of OA. And higher levels of ITIH1, EFEMP1, and ERLEC1 were associated with decreased risk of hip OA., Conclusion: Our study provides new insights into the genetic component of protein abundance in OA and a promising therapeutic target for future drug development., (© 2024. The Author(s).)

Purpose: Osteoarthritis (OA) is a common degenerative joint disease, with its etiology remaining poorly understood. Our study aims to explore the causal associations between immune cells and OA, with the goal of generating a new perspective for targeted intervention strategies., Methods: A bidirectional two-sample Mendelian randomization (MR) analysis was performed to estimate the causality between multiple circulating immune cells and different sites of OA. The immune cell traits analyzed included the counts of circulating white blood cells (WBC), lymphocytes, monocytes, neutrophils, eosinophils, and basophils, as well as certain subsets of T and B lymphocytes. The OA types included were OA at any site, knee OA, hip OA, spine OA, thumb OA, and hand OA. Inverse-variance weighted (IVW), MR-Egger, weight median and weight mode were used to evaluate causal effects, with IVW being the main analysis method. Sensitivity analyses were conducted to assess heterogeneity and pleiotropy., Results: Our findings indicated that resting regulatory T cell (Treg) absolute counts (AC) were causally associated with an increased risk for spine OA [odds ratio (OR), 1.051; 95 % confidence interval (CI), 1.018-1.086; P=0.0005, P FDR =0.0350], and spine OA showed a positive causal relationship with the neutrophils count (OR, 1.104; 95 %CI, 1.032-1.181; P=0.0039, P FDR =0.0233). Besides, OA at any site was correlated with a rise in circulating eosinophils count (OR, 1.05; 95 %CI, 1.021-1.079; P=0.0007, P FDR =0.0041), while knee OA was associated with decreased total WBC (OR, 0.945; 95 %CI, 0.912-0.979; P=0.0016, P FDR =0.0048) and monocytes counts (OR, 0.958; 95 %CI, 0.934-0.982; P=0.0007, P FDR  = 0.0041). No evidence of heterogeneity or horizontal pleiotropy was detected., Conclusions: Our study has demonstrated the causal associations between multiple immune cells and diverse joint OA. These results highlight the intricate interplay between immune cells and OA, suggesting potential targets for therapeutic interventions to manage disease progression and alleviate symptoms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The association between insulin resistance (IR) and the risk of all-cause mortality and cardiovascular mortality among osteoarthritis (OA) patients remains uncertain. This study aims to clarify the correlation between a novel marker of IR, the triglyceride glucose-body mass index (TyG-BMI), and the risk of all-cause mortality and cardiovascular mortality in OA patients. Data from the National Health and Nutrition Examination Survey (NHANES) spanning from 1999 to 2020 were analyzed. Multivariable Cox proportional hazards regression analysis and restricted cubic spline plots were employed to elucidate the association between the TyG-BMI index and the risk of all-cause mortality or cardiovascular mortality in OA patients. Additionally, subgroup analysis was conducted to explore potential interactions and identify populations at elevated risk of mortality. The study cohort comprised 4097 OA patients who were followed up for a period of 20 years, during which 1197 cases of all-cause mortality and 329 cases of mortality attributed to cardiovascular disease were recorded. Our findings revealed a U-shaped nonlinear relationship between the TyG-BMI index and the risk of all-cause mortality or cardiovascular mortality in OA patients, with the lowest mortality risk thresholds identified at 282 and 270, respectively. Moreover, surpassing these thresholds was associated with a 3% increase in the risk of all-cause mortality and a 5% increase in the risk of cardiovascular mortality for every 10-unit increment in TyG-BMI level. Among American OA patients, a U-shaped nonlinear relationship exists between the TyG-BMI index and the risk of all-cause mortality or cardiovascular mortality. These findings underscore the significant role of IR in the progression of OA., (© 2024. The Author(s).)

Background: Osteoarthritis is a prevalent musculoskeletal condition, but the role of specific serum biomarkers, such as calcium, vitamin D, and C-reactive protein (CRP), in predicting mortality among individuals with osteoarthritis remains unclear., Methods: This observational study analyzed longitudinal data from over 500,000 participants in the UK Biobank, identifying those with osteoarthritis using ICD-9/10 codes or self-reported history. We performed multivariable cox-regression and flexible parametric survival model (FPSM) for survival analysis, with adjustments made through the inverse probability of treatment weight (IPTW) for baseline covariates identified by directed acyclic graphs (DAGs)., Results: Of the 49,082 osteoarthritis population, the average age was 60.69 years, with 58.7% being female. During the follow-up period exceeding 15 years, a total of 5,522 people with osteoarthritis died. High serum calcium levels, compared to normal serum calcium levels, were significantly associated with all-cause mortality (hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.11, 1.59), cardiovascular diseases (CVD)-related deaths (HR 1.55, 95% CI 1.05, 2.29), and other deaths (HR 1.59, 95% CI 1.20, 2.11). Low serum calcium levels, compared to normal serum calcium levels, was linked with CVD-related deaths (HR 2.06, 95% CI 1.02, 4.14). Vitamin D insufficiency, compared to sufficient vitamin D levels, was correlated with all-cause mortality (HR 1.22, 95% CI 1.13, 1.33), CVD-related deaths (HR 1.43, 95% CI 1.20, 1.72), and other deaths (HR 1.26, 95% CI 1.09, 1.45) but not with cancer-related deaths. High serum CRP levels, compared to normal CRP levels, were associated with all outcomes (all-cause mortality: HR 1.22, 95% CI 1.12, 1.33; CVD-related death: HR 1.24, 95%CI 1.03, 1.49; cancer-related death: HR 1.23, 95% CI 1.09, 1.40; other deaths: HR 1.19, 95%CI 1.03, 1.38)., Conclusions: Both high and low serum calcium levels, elevated CRP, and vitamin D insufficiency are potential predictors of increased mortality risk in the osteoarthritis population. These findings emphasize the importance of monitoring and possibly addressing these serum biomarkers in osteoarthritis populations to improve long-term outcomes. Further studies are needed to understand the underlying mechanisms and to propose therapeutic interventions., (© 2024. The Author(s).)

Background: Osteoarthritis (OA) is a global public health problem, and limited information is available on the effects of Cd on OA. The purpose of this study is to explore the relationship between Cd and OA., Method: Weighted multivariable logistic regression model, trend test, restricted cubic spline, and stratified analysis were used to study the association between BCd and OA., Results: In the two regression models of weighted multivariable logistic regression analysis, the correlation between BCd and OA was positive. Compared with the lowest quartile of BCd exposure, the highest quartile had a 2.03-fold (95% confidence interval, 1.67 to 2.47), displaying a dose-response relationship (P for trend <0.00001). The restrictive cubic spline shows a positive linear relationship between BCd and OA., Conclusion: There was a positive linear relationship between BCd and OA and a dose-response relationship., Competing Interests: Conflicts of interest: none declared., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine.)

Purpose: To investigate the incidence of periprosthetic joint infection (PJI) in patients with rheumatoid arthritis (RA) or osteoarthritis (OA) after primary joint arthroplasty; to analyze the optimal cut-off values of clinical serum markers C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and D-dimer for the diagnosis of PJI in RA patients; and to explore their diagnostic efficacy and clinical significance., Methods: Clinical data of 15,702 patients with RA (578) or OA (15,124) who underwent total joint arthroplasty from 2013 to 2021 were retrospectively analyzed. Serum CRP, ESR, and D-dimer were recorded for each patient, and subject characteristic curves were used to determine the optimal threshold values of CRP, ESR, and D-dimer for RA-PJI and OA-PJI and to compare the areas under the curves to assess the diagnostic efficacy of the optimal threshold values of serologic indices for RA-PJI., Results: The five year incidence of PJI was 6.92% in RA patients and 0.67% in OA patients. The optimal thresholds of CRP, ESR, and D-dimer for the diagnosis of RA-PJI were respectively 13.85 mg/L, 33.02 mm/h, and 796.50 ng/mL. The sensitivities of the optimal thresholds were respectively 67.6%, 62.2%, and 56.8%, and the specificities were 74.7%, 60.4%, and 74.4%., Conclusion: RA patients have a higher incidence of PJI than OA patients. The optimal thresholds for CRP, ESR, and d-dimer for the diagnosis of PJI were higher in RA patients than in OA patients, but the sensitivity and specificity of the diagnosis were not as good as in OA patients., (© 2024. The Author(s) under exclusive licence to SICOT aisbl.)

Osteoarthritis (OA), a prevalent degenerative joint disease, significantly affects the well-being of afflicted individuals and compromises the standard functionality of human joints. The emerging biomarker, Cartilage acidic protein 1 (CRTAC1), intricately associates with OA initiation and serves as a prognostic indicator for the trajectory toward joint replacement. However, existing diagnostic methods for CRTAC1 are hampered by the limited abundance, thus restricting the precision and specificity. Herein, a novel approach utilizing a single-walled carbon nanotube field-effect transistor (SWCNTs FET) biosensor is reported for the direct label-free detection of CRTAC1. High-purity semiconducting carbon nanotube films, functionalized with antibodies of CRTAC1, provide excellent electrical and sensing properties. The SWCNTs FET biosensor exhibits high sensitivity, notable reproducibility, and a wide linear detection range (1 fg/mL to 100 ng/mL) for CRTAC1 with a theoretical limit of detection (LOD) of 0.2 fg/mL. Moreover, the SWCNTs FET biosensor is capable of directly detecting human serum samples, showing excellent sensing performance in differentiating clinical samples from OA patients and healthy populations. Comparative analysis with traditional enzyme-linked immunosorbent assay (ELISA) reveals that the proposed biosensor demonstrates faster detection speeds, higher sensitivity/accuracy, and lower errors, indicating high potential for the early OA diagnosis. Furthermore, the SWCNTs FET biosensor has good scalability for the combined diagnosis and measurement of multiple disease markers, thereby significantly expanding the application of SWCNTs FETs in biosensing and clinical diagnostics.

Background: Previous traditional observational studies have suggested the contribution of several cytokines and growth factors to the development of osteoarthritis (OA). This study aimed to determine the association of circulating cytokine and growth factor levels with OA., Methods: We used two-sample Mendelian randomization (MR) to explore the causality between circulating cytokine and growth factor levels and OA [including knee or hip OA (K/HOA), knee OA (KOA), and hip OA (HOA)]. Summary level data for circulating cytokine and growth factor levels were sourced from a genome-wide association study (GWAS) involving 8,293 participants of Finnish ancestry. Single-nucleotide polymorphisms related to K/HOA (39,427 cases and 378,169 controls), KOA (24,955 cases and 378,169 controls), and HOA (15,704 cases and 378,169 controls) were obtained from a previous GWAS. The inverse variance weighted (IVW) method was primarily used for our MR analysis. For exposures to only one relevant SNP as IV, we used the Wald ratio as the major method to assess causal effects. We also conducted a series of sensitivity analyses to improve the robustness of the results., Results: Circulating vascular endothelial growth factor levels were suggestively associated with an increased risk of K/HOA (odds ratio (OR) = 1.034; 95 % confidence interval (CI) = 1.013-1.055; P = 0.001), KOA (OR = 1.034; 95 % CI = 1.014-1.065; P = 0.002), and HOA (OR = 1.039; 95 % CI = 1.003-1.067; P = 0.034). Circulating interleukin (IL)-12p70 levels was suggestively associated with K/HOA (OR = 1.047; 95 % CI = 1.018-1.077; P = 0.001), KOA (OR = 1.058; 95 % CI = 1.022-1.095; P = 0.001), and HOA (OR = 1.044; 95 % CI = 1.000-1.091; P = 0.048). Circulating IL-18 levels were suggestively associated with HOA (OR = 1.068; 95 % CI = 1.014-1.125; P = 0.012). However, limited evidence exists to support causal genetic relationships between other circulating cytokines, growth factor levels and K/HOA, KOA, and HOA., Conclusions: Our MR analysis provides suggestive evidence of causal relationships between circulating cytokines and growth factors levels and OA, providing new insights into the etiology of OA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic inflammation may contribute to increased mortality risk in individuals with osteoarthritis (OA), but research on the prognostic value of inflammatory biomarkers is limited. We aimed to evaluate the associations of the systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI) with all-cause and cardiovascular mortality among US adults with OA., Methods: This cohort study included 3545 adults with OA aged ≥ 20 years from the National Health and Nutrition Examination Survey 1999-2020. The SII and SIRI were calculated using complete blood cell count data. Participants were categorized as having a higher or lower SII and SIRI using cutoff points derived by the maximally selected rank statistics method. Cox proportional hazards models, Fine-Gray competing risk regression models and time-dependent receiver operating characteristic (ROC) analysis were used to evaluate the associations between the SII/SIRI and mortality in OA patients., Results: Over a median follow-up of 5.08 (3.42-9.92) years, 636 (17.94%) deaths occurred, including 149 (4.20%) cardiovascular deaths. According to multivariable-adjusted models involving demographic, socioeconomic, and health factors, OA patients with a higher SII had a twofold greater risk of all-cause mortality than patients with a lower SII (HR 2.01; 95% CI: 1.50-2.68). Similarly, a higher SIRI was associated with an 86% increased risk of all-cause mortality relative to a lower SIRI (HR 1.86; 95% CI: 1.46-2.38). Similar to the trend found with all-cause mortality, patients with an elevated SII and SIRI had a 88% and 67% increased risk of cardiovascular mortality, respectively, compared to patients with a lower SII (HR 1.88; 95% CI: 1.16-3.03) and SIRI (HR 1.67; 95% CI: 1.14-2.44). Time-dependent ROC curves showed that both the SII and SIRI have moderate and valid performance in predicting short- and long-term mortality in patients with OA., Conclusions: Higher SII and SIRI values were associated with greater all-cause and cardiovascular mortality among US adults with OA., (© 2024. The Author(s).)

Background: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that leads to joint destruction. Numerous pro-inflammatory mediators, including adipokines, play an important role in the pathogenesis of RA., Objective: The aim of the study was to investigate the relationships between selected plasma cytokines and expression of adiponectin and its receptors in the synovium and the infrapatellar fat pad in patients with RA and osteoarthritis (OA)., Methods: Blood, synovium and fat pad samples from 18 patients with RA and 18 with OA were collected during joint replacement surgery. Spearman rank correlations between plasma concentrations of selected cytokines (IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 p40, IL-13, IL-17, G-CSF and GM-CSF) and the expression of adiponectin and its receptors were determined. Plasma levels of cytokines were determined using a magnetic bead-based multiplex assay, mRNA expression of adiponectin and its receptors were determined by real-time PCR., Results: In OA patients, there were significant positive correlations between adiponectin expression in the synovial membrane and plasma levels of IL-1β, IL-4, G-CSF and GM-CSF, as well as a significant positive correlation between adiponectin expression in the fat pad and plasma levels of GM-CSF. In addition, OA patients showed significant negative correlations between AdipoR1 and AdipoR2 expression in the synovial membrane and plasma IL-6 levels, as well as between AdipoR2 expression in the synovial membrane and plasma MCP-1 and TNF-α levels. In patients with RA, there were no significant correlations between adiponectin expression in the synovial membrane and infrapatellar fat pad and plasma levels of the cytokines studied. In addition, RA patients showed a statistically significant negative correlation between AdipoR1 expression in the synovial membrane and plasma levels of TNF-α, IL-7, IL-12 and IL-13, and a significant negative correlation between AdipoR1 expression in the infrapatellar fat pad and plasma levels of IL-1β., Conclusions: Adiponectin and its receptors showed the correlations with several plasma cytokines, however, a thorough understanding of the role of adiponectin in RA and OA requires further investigation., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: As individuals age, the prevalence of osteoarthritis tends to increase gradually. α-Klotho is a hormone renowned for its anti-aging properties. However, the precise role of serum α-Klotho in osteoarthritis is still not fully comprehended., Methods: We conducted a cross-sectional study utilizing data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2007 to 2016. Serum α-Klotho levels were measured using an enzyme-linked immunosorbent assay (ELISA). Osteoarthritis was assessed through self-reported questionnaires. Through univariate and multivariate logistic regression analyses, smooth curve fitting, threshold effect analysis, and subgroup analyses, we delved into the potential association between them., Results: The study encompassed a cohort of 10,265 participants. In fully adjusted models of multivariate logistic regression analysis, we identified a negative correlation between serum ln α-Klotho and OA (OR = 0.77, 95% CI: 0.65-0.91, p = 0.003). When stratifying serum α-Klotho levels into tertiles, individuals in the highest tertile exhibited a 26% reduced risk of OA compared to those in the lowest tertile (OR = 0.84, 95% CI: 0.73-0.97, p = 0.014). Subsequent analyses indicated a linearly negative association. In subgroup analyses, we explored the relationship between serum ln α-Klotho and osteoarthritis across diverse populations, revealing the persistence of this association in the majority of subgroups., Conclusion: Serum α-Klotho levels exhibit a significant negative linear correlation with the prevalence of osteoarthritis in middle-aged and elderly populations in the United States., (Copyright © 2024 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)

In this study of the alterations of Glypicans 1 to 6 (GPCs) and Notum in plasma, bone marrow mesenchymal stromal cells (BM-MSCs) and osteoblasts in Osteoarthritis (OA), the levels of GPCs and Notum in the plasma of 25 patients and 24 healthy subjects were measured. In addition, BM-MSCs from eight OA patients and eight healthy donors were cultured over a period of 21 days using both a culture medium and an osteogenic medium. Protein and gene expression levels of GPCs and Notum were determined using ELISA and qPCR at 0, 7, 14 and 21 days. GPC5 and Notum levels decreased in the plasma of OA patients, while the BM-MSCs of OA patients showed downexpression of GPC6 and upregulation of Notum. A decrease in GPC5 and Notum proteins and an increase in GPC3 were found. During osteogenic differentiation, elevated GPCs 2, 4, 5, 6 and Notum mRNA levels and decreased GPC3 were observed in patients with OA. Furthermore, the protein levels of GPC2, GPC5 and Notum decreased, while the levels of GPC3 increased. Glypicans and Notum were altered in BM-MSCs and during osteogenic differentiation from patients with OA. The alterations found point to GPC5 and Notum as new candidate biomarkers of OA pathology.

Background: Osteoarthritis (OA) is a chronic degenerative joint disease causing limited mobility and pain, with no curative treatment available. Recent in vivo studies suggested autonomic alterations during OA progression in patients, yet clinical evidence is scarce. Therefore, autonomic tone was analyzed in OA patients via heart rate variability (HRV) measurements., Methods: Time-domain (SDRR, RMSSD, pRR50) and frequency-domain (LF, HF, LF/HF) HRV indices were determined to quantify sympathetic and parasympathetic activities. In addition, perceived stress, WOMAC pain as well as serum catecholamines, cortisol and dehydroepiandrosterone-sulphate (DHEA-S) were analyzed. The impact of the grade of disease (GoD) was evaluated by linear regression analysis and correlations with clinical data were performed., Results: GoD significantly impacted the autonomic tone in OA patients. All time-domain parameters reflected slightly decreased HRV in early OA patients and significantly reduced HRV in late OA patients. Moreover, frequency-domain analysis revealed decreased HF and LF power in all OA patients, reflecting diminished parasympathetic and sympathetic activities. However, LF/HF ratio was significantly higher in early OA patients compared to late OA patients and implied a clear sympathetic dominance. Furthermore, OA patients perceived significantly higher chronic stress and WOMAC pain levels compared to healthy controls. Serum cortisol and cortisol/DHEA-S ratio significantly increased with GoD and positively correlated with WOMAC pain. In contrast, serum catecholamines only trended to increase with GoD and pain level., Conclusions: This prospective study provides compelling evidence of an autonomic dysfunction with indirect sympathetic dominance in early and late knee OA patients for the first time based on HRV analyses and further confirmed by serum stress hormone measurements. Increased sympathetic activity and chronic low-grade inflammation in OA as well as in its major comorbidities reinforce each other and might therefore create a vicious cycle. The observed autonomic alterations coupled with increased stress and pain levels highlight the potential of HRV as a prognostic marker. In addition, modulation of autonomic activity represents an attractive future therapeutic option., (© 2024. The Author(s).)

Background: The association between the systemic immune-inflammation index (SII) and the serum soluble-Klotho concentration (pg/ml) in osteoarthritis (OA) patients is unknown. This study aimed to investigate the relationship between the SII and serum soluble-Klotho levels in OA patients., Methods: All study data were obtained from the National Health and Nutrition Examination Survey (NHANES) database (n = 1852 OA patients; age range = 40-79 years). The SII and serum Klotho measurement data are from the NHANES mobile examination centre. The SII values were divided into quartiles (Q1-4: 0.02-3.36, 3.36-4.78, 4.79-6.70, and 6.70-41.75). A multivariate linear regression model was constructed to evaluate the association between the SII and serum Klotho levels in OA patients; interaction tests were conducted to test the stability of the statistical results., Results: Multivariate linear regression revealed a negative linear relationship between the SII and serum Klotho concentration in OA patients (β = -6.05; 95% CI: -9.72, -2.39). Compared to Q1, Q4 was associated with lower serum Klotho concentrations (β = -59.93; 95% CI: -96.57, -23.28). Compared with that of Q1, the β value of Q2-Q4 showed a downwards trend as the SII increased (Ptrend <0.001). The stratified analysis results indicated that the SII had a greater sensitivity in predicting serum Klotho concentrations in OA patients aged 60-79 years (Pinteraction = 0.028)., Conclusions: There was a significant negative linear correlation between the SII and serum Klotho concentration in OA patients. The SII can serve as a predictive indicator of serum Klotho concentrations in OA patients. Klotho may be a potential anti-inflammatory drug for OA treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Seronegative rheumatoid arthritis (RA) is defined as RA without circulating autoantibodies such as rheumatoid factor and anti-citrullinated protein antibodies; thus, early diagnosis of seronegative RA can be challenging. Here, we aimed to identify diagnostic biomarkers for seronegative RA by performing lipidomic analyses of sera and urine samples from patients with RA., Methods: We performed untargeted lipidomic analysis of sera and urine samples from 111 RA patients, 45 osteoarthritis (OA) patients, and 25 healthy controls (HC). These samples were divided into a discovery cohort (n = 97) and a validation cohort (n = 84). Serum samples from 20 patients with systemic lupus erythematosus (SLE) were also used for validation., Results: The serum lipidome profile of RA was distinguishable from that of OA and HC. We identified a panel of ten serum lipids and three urine lipids in the discovery cohort that showed the most significant differences. These were deemed potential lipid biomarker candidates for RA. The serum lipid panel was tested using a validation cohort; the results revealed an accuracy of 79%, a sensitivity of 71%, and a specificity of 86%. Both seropositive and seronegative RA patients were differentiated from patients with OA, SLE, and HC. Three urinary lipids showing differential expression between RA from HC were identified with an accuracy of 84%, but they failed to differentiate RA from OA. There were five lipid pathways that differed between seronegative and seropositive RA., Conclusion: Here, we identified a panel of ten serum lipids as potential biomarkers that can differentiate RA from OA and SLE, regardless of seropositivity. In addition, three urinary lipids had diagnostic utility for differentiating RA from HC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Koh, Park, Choi and Kim.)

The causal association between vitamin E status and osteoarthritis (OA) remains controversial in previous epidemiological studies. We employed a Mendelian randomization (MR) analysis to explore the causal relationship between circulating alpha-tocopherol levels (main forms of vitamin E in our body) and OA. The instrumental variables (IVs) of circulating alpha-tocopherol levels were obtained from a Genome-wide association study (GWAS) dataset of 7781 individuals of European descent. The outcome of OA was derived from the UK biobank. Two-sample MR analysis was used to estimate the causal relationship between circulating alpha-tocopherol levels and OA. The inverse-variance weighted (IVW) method was the primary analysis in this analysis. We used the MR-Egger method to determine horizontal pleiotropic in this work. The heterogeneity effect of instrumental IVs was detected by MR-Egger and IVW analyses. Sensitivity analysis was performed by removing single nucleotide polymorphism (SNP) one by one. Three SNPs (rs964184, rs2108622, and rs11057830) (P < 5E-8) strongly associated with circulating alpha-tocopherol levels were used in this analysis. The IVW-random effect indicated no causal relationship between circulating alpha-tocopherol levels and clinically diagnosed OA (OR = 0.880, 95% CI 0.626, 1.236, P = 0.461). Similarly, IVW analysis showed no causal association between circulating alpha-tocopherol levels and self-reported OA (OR = 0.980, 95% CI 0.954, 1.006, P = 0.139). Other methods of MR analyses and sensitivity analyses revealed consistent findings. MR-Egger and IVW methods indicated no significant heterogeneity between IVs. The MR-Egger intercept showed no horizontal pleiotropic. The results of this linear Mendelian randomization study indicate no causal association between genetically predicted alpha-tocopherol levels and the progression of OA. Alpha-tocopherol may not provide beneficial and more favorable outcomes for the progression of OA. Further MR analysis based on updated GWASs with more IVs is required to verify the results of our study., (© 2024. The Author(s).)

PsoP27 is an antigen expressed in psoriatic lesions. It plays an inflammatory role in psoriasis. This study objective was to characterize antibodies (Abs) against PsoP27 in patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA). Levels of Abs against native and citrullinated PsoP27 in PsA and RA patients' synovial fluid (SF) and sera were determined by ELISA. SF of osteoarthritis (OA) patients and sera of healthy donors were used as controls. Levels of Abs against PsoP27 were correlated with disease activity scores. Abs against native and citrullinated PsoP27 levels in SF of PsA ( n  = 48; 0.38 ± 0.03 and 0.44 ± 0.04, respectively) and RA ( n  = 22; 0.57 ± 0.1 and 0.62 ± 0.09, respectively) were significantly higher than in OA patients ( n  = 23; 0.14 ± 0.01 and 0.15 ± 0.01, respectively) ( p  < .0001). For both Abs, there were no significant differences between their level in PsA and RA patients. There was no difference in the level of Abs against citrullinated PsoP27 in SF of seronegative versus seropositive RA patients. Levels of Abs against both native and citrullinated PsoP27 in the SF and level of systemic C-reactive protein in PsA correlated positively, while in RA there were no significant correlations with disease activity scores. No differences in level of Abs against PsoP27 were found in the sera of all three study groups. Abs against native and citrullinated PsoP27 are present in PsA and RA SF but not in those of OA patients, suggesting a potential role of those Abs in inflammatory joint diseases.

Objective: The purpose of this study was to explore the relationship between serum uric acid (SUA) concentrations and all-cause mortality in individuals with osteoarthritis (OA)., Methods: All participant data were retrieved from the National Health and Nutrition Examination Survey database. A total of 4671 participants (age range: 20 to 85 years old), including 2988 females and 1683 males, were included in this study. The determination of death outcome was based on the National Death Index (up to December 31, 2019). We explored the nonlinear relationship between SUA concentrations and all-cause mortality in OA patients by establishing a Cox proportional risk model and a two-segment Cox proportional risk model and ran an interaction test to identify the high-risk population for all-cause mortality., Results: During 30,645 person-years of follow-up, the number of all-cause deaths for females and males was 736 and 516, respectively. After multivariate adjustment, we found a nonlinear relationship between SUA concentrations and all-cause mortality in both females and males with OA. In addition, we found a J-shaped relationship between SUA concentrations and all-cause mortality. The SUA concentration thresholds for all-cause mortality of females and males were stable at 5.6mg/dl and 6.2mg/dl, respectively. Compared with SUA concentrations below the inflection point, the all-cause mortality risk at higher SUA concentrations in females and males with OA increased by 20% (hazard ratio [HR]: 1.2, 95% confidence interval [CI]: 1.1 to 1.2) and 25% (HR: 1.2, 95% CI: 1.12 to 1.39), respectively., Conclusions: There is a nonlinear relationship between SUA concentrations and all-cause mortality in the American OA population (J-shaped association). The all-cause mortality thresholds for SUA concentrations in females and males are 5.6mg/dl and 6.2mg/dl, respectively., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: People with osteoarthritis place a huge burden on society. Early diagnosis is essential to prevent disease progression and to select the best treatment strategy more effectively. In this study, the aim was to examine the diagnostic features and clinical value of peripheral blood biomarkers for osteoarthritis., Objective: The goal of this project was to investigate the diagnostic features of peripheral blood and immune cell infiltration in osteoarthritis (OA)., Methods: Two eligible datasets (GSE63359 and GSE48556) were obtained from the GEO database to discern differentially expressed genes (DEGs). The machine learning strategy was employed to filtrate diagnostic biomarkers for OA. Additional verification was implemented by collecting clinical samples of OA. The CIBERSORT website estimated relative subsets of RNA transcripts to evaluate the immune-inflammatory states of OA. The link between specific DEGs and clinical immune-inflammatory markers was found by correlation analysis., Results: Overall, 67 robust DEGs were identified. The nuclear receptor subfamily 2 group C member 2 (NR2C2), transcription factor 4 (TCF4), stromal antigen 1 (STAG1), and interleukin 18 receptor accessory protein (IL18RAP) were identified as effective diagnostic markers of OA in peripheral blood. All four diagnostic markers showed significant increases in expression in OA. Analysis of immune cell infiltration revealed that macrophages are involved in the occurrence of OA. Candidate diagnostic markers were correlated with clinical immune-inflammatory indicators of OA patients., Conclusion: We highlight that DEGs associated with immune inflammation (NR2C2, TCF4, STAG1, and IL18RAP) may be potential biomarkers for peripheral blood in OA, which are also associated with clinical immune-inflammatory indicators., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: To the best of our knowledge, the present study is the first in the literature to assess distal femoral cartilage thickness and its relationship with ferritin levels in adult patients with beta thalassaemia major (BTM)., Materials and Methods: 45 patients with BTM and 45 healthy controls were included in the study. Ferritin and haemoglobin levels of the patient and healthy groups were determined by blood analysis and distal femoral cartilage thicknesses were measured via ultrasound. Then, the patient group was divided into subgroups according to whether their ferritin levels were below or above 2500 µg/L. They were then compared among themselves and with the healthy control group using the available data., Results: Distal femoral cartilage thickness values were statistically significantly lower in the BTM group compared to the healthy control group (p values < 0.001). Patients with a ferritin level below 2500 µg/L had statistically significantly higher right and left average distal femoral cartilage thickness values than the patients with a ferritin level above 2500 µg/L (p = 0.029 and p = 0.019, respectively). The right and left average distal femoral cartilage thickness values of the patient subgroup with low ferritin levels were statistically similar to the control group (p = 0.146 and p = 0.164, respectively)., Conclusion: Our study showed that thalassaemia patients are more likely to develop osteoarthritis (OA) than the normal population and possible OA development can be prevented by keeping the ferritin levels of these patients in the optimum range., (© 2022. The Japanese Society Bone and Mineral Research.)

Objective: To summarize recent scientific advances in protein-derived soluble biomarkers of osteoarthritis., Design: A systematic search on the PubMed electronic database of clinical studies on protein-derived soluble biochemical markers of osteoarthritis in humans that were published between January 1st 2020 and March 31th 2021. The studies were selected on the basis of objective criteria and summarized in a table. Then they were described in a narrative review., Results: Out of 1971 publications, 48 fulfilled all selection criteria and 16 were selected by the author for the narrative review. The papers were classified according their clinical significance as defined in the BIPEDS classification. Two papers investigated the "burden of disease", two were dedicated to "investigative biomarkers", four papers question the "prognosis", three the "efficacy of treatment" and five the "diagnosis and phenotyping" value of protein-derived biomarkers., Conclusions: Currently, biomarkers research is focused on their use as tools to identify molecular endotypes and clinical phenotypes and to facilitate patient screening and monitoring in clinical trials. This approach should allow a more targeted management of patients suffering from osteoarthritis., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To detect the serum level of soluble chemokines CXCL9 and CXCL10 in patients with rheumatoid arthritis (RA), and to analyze their correlation with bone erosion, as well as the clinical significance in RA., Methods: In the study, 105 cases of RA patients, 90 osteoarthritis (OA) patients and 25 healthy controls in Peking University People's Hospital were included. All the clinical information of the patients was collected, and the serum CXCL9 and CXCL10 levels of both patients and healthy controls were measured by enzyme-linked immune sorbent assay (ELISA). CXCL9 and CXCL10 levels among different groups were compared. The correlation between serum levels with clinical/laboratory parameters and the occurrence of bone erosion in RA were analyzed. Independent sample t test, Chi square test, Mann-Whitney U test, Spearman's rank correlation and Logistic regression were used for statistical analysis., Results: The levels of CXCL9 and CXCL10 were significantly higher in the RA patients [250.02 (126.98, 484.29) ng/L, 108.43 (55.16, 197.17) ng/L] than in the OA patients [165.05 (75.89, 266.37) ng/L, 69.00 (33.25, 104.74) ng/L] and the health controls [79.47 (38.22, 140.63) ng/L, 55.44 (18.76, 95.86) ng/L] (all P < 0.01). Spearman's correlation analysis showed that the level of serum CXCL9 was positively correlated with swollen joints (SJC), rheumatoid factor (RF) and disease activity score 28 (DAS28) ( r =0.302, 0.285, 0.289; P =0.009, 0.015, 0.013). The level of serum CXCL10 was positively correlated with tender joints (TJC), SJC, C-reactive protein (CRP), immunoglobulin (Ig) A, IgM, RF, anti-cyclic citrullinated peptide antibody (ACPA), and DAS28 ( r =0.339, 0.402, 0.269, 0.266, 0.345, 0.570, 0.540, 0.364; P =0.010, 0.002, 0.043, 0.045, 0.009, < 0.001, < 0.001, 0.006). Serum CXCL9 and CXCL10 levels in the RA patients with bone erosion were extremely higher than those without bone erosion [306.84 (234.02, 460.55) ng/L vs. 149.90 (75.88, 257.72) ng/L, 153.74 (89.50, 209.59) ng/L vs. 54.53 (26.30, 83.69) ng/L, respectively] (all P < 0.01). Logistic regression analysis showed that disease duration, DAS28 and serum level of CXCL9 were correlated with bone erosion in the RA patients ( P < 0.05)., Conclusion: Serum levels of CXCL9 and CXCL10 were remarkably elevated in patients with RA, and correlated with disease activities and occurrence of bone erosion. Chemokines CXCL9 and CXCL10 might be involved in the pathogenesis and bone destruction in RA.

Osteoarthritis is a common multifactorial chronic disease that occurs in articular cartilage, subchondral bone, and periarticular tissue. The pathogenesis of OA is still unclear. To investigate the differences in serum metabolites between OA and the control group, liquid chromatography/mass spectrometry (LC/MS)-based metabolomics was used. To reveal the pathogenesis of OA, 12 SD male rats were randomly divided into control and OA groups using collagenase to induce OA for modeling, and serum was collected 7 days after modeling for testing. The OA group was distinguished from the control group by principal component analysis and orthogonal partial least squares-discriminant analysis, and six biomarkers were finally identified. These biomarkers were metabolized through tryptophan metabolism, glutamate metabolism, nitrogen metabolism, spermidine metabolism, and fatty acid metabolism pathways. The study identified metabolites that may be altered in OA, suggesting a role in OA through relevant metabolic pathways. Metabolomics, as an important tool for studying disease mechanisms, provides useful information for studying the metabolic mechanisms of OA.

Objective: Biomarkers for diagnosis and progression of osteoarthritis (OA) are lacking. This study was undertaken to identify circulating biomarkers for OA that could predict disease occurrence and/or progression to joint replacement., Methods: Using the SomaScan platform, we measured 4,792 proteins in plasma from 37,278 individuals, of whom 12,178 individuals had OA and 2,524 had undergone joint replacement. We performed a case-control study for identification of potential protein biomarkers for hip, knee, and/or hand OA, and a prospective study for identification of biomarkers for joint replacement., Results: Among the large panel of plasma proteins assessed, cartilage acidic protein 1 (CRTAC1) was the most strongly associated with both OA diagnosis (odds ratio 1.46 [95% confidence interval 1.41-1.52] for knee OA, odds ratio 1.36 [95% confidence interval 1.29-1.43] for hip OA, and odds ratio 1.33 [95% confidence interval 1.26-1.40] for hand OA) and progression to joint replacement (hazard ratio 1.40 [95% confidence interval 1.30-1.51] for knee replacement and hazard ratio 1.31 [95% confidence interval 1.19-1.45] for hip replacement). Patients with OA who were in the highest quintile of risk of joint replacement, based on known risk factors (i.e., age, sex, and body mass index) and plasma CRTAC1 level, were 16 times more likely to undergo knee replacement within 5 years of plasma sample collection than those in the lowest quintile, and 6.5 times more likely to undergo hip replacement. CRTAC1 was not associated with other types of inflammatory arthritis. A specific protein profile was identified in those patients who had undergone joint replacement prior to plasma sample collection., Conclusion: Through a hypothesis-free approach, we identified CRTAC1 in plasma as a novel promising candidate biomarker for OA that is both associated with occurrence of OA and predictive of progression to joint replacement. This biomarker might also be useful in the selection of suitable patients for clinical trial enrollment., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Osteoarthritis (OA) is a primary leading cause of pain and disability. However, some cases are diagnosed at the later stage which delayed the timely treatment. This study aims to identify effective diagnostic signature for OA. The mRNA profile GSE48566 including 106 blood samples of OA patients and 33 blood samples of healthy individuals was downloaded from Gene Expression Omnibus (GEO) database. The potential OA-related genes were screened by weighted gene co-expression network analysis (WGCNA). Gene ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to reveal the functions or pathways of OA-related genes using the clusterProfiler function package of R software. Key genes significantly involved in OA progression were further screened by protein-protein interaction (PPI) network. The logistic regression model and the random forest model were conducted by bringing into optimal genes selected by stepwise regression analysis, and fivefold cross validation method was used to determine their reliability. A total of 146 genes, existed in three modules and might be associated with the occurrence of OA, were screened. 15 genes were screened from the PPI network and four genes, including CCR6, CLEC7A, IL18 and SRSF2, were further optimized. Finally, a logistic regression model and a random forest model were conducted by bringing into four optimal genes, and could reliably separate OA patients from healthy subjects. Our study established two effective diagnostic models based on CCR6, CLEC7A, IL18 and SRSF2, which could reliably separate OA patients from healthy subjects., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

The rising incidence of bone pathologies such as osteoporosis and osteoarthritis is negatively affecting the functional status of millions of patients worldwide. The genetic component of these multifactorial pathologies is far from being fully understood, but in recent years several epigenetic mechanisms involved in the pathophysiology of these bone diseases have been identified. The aim of the present study was to compare the serum expression of four miRNAs in women with hip fragility fracture (OF group), osteoarthritis requiring hip replacement (OA group) and control women (Ctrl group). Serum expression of miR-497-5p, miR-155-5p, miR-423-5p and miR-365-3p was determined in a sample of 23 OA women, 25 OF women and 52 Ctrl women. Data shown that women with bone pathologies have higher expression of miR-497 and miR-423 and lower expression of miR-155 and miR-365 than control subjects. Most importantly, miR-497 was identified as an excellent discriminator between OA group and control group (AUC: 0.89, p < 0.000) and acceptable in distinguishing from the OF group (AUC: 0.76, p = 0.002). Our data suggest that circulating miR-497 may represent a significant biomarker of OA, a promising finding that could contribute towards future early-stage diagnosis of this disease. Further studies are required to establish the role of miR-155, miR-423 and miR-365 in bone pathologies., (© 2021. The Author(s).)

Biomarkers are essential tools in osteoarthritis (OA) research, clinical trials, and drug development. Detecting and evaluating biomarkers in OA research can open new avenues for researching and developing new therapeutics. In the present report, we have explored the serological detection of various osteoarthritis-related biomarkers in the preclinical model of OA. In this surgical OA model, we disrupted the medial tibial cartilage's integrity via anterior cruciate ligament transection combined with medial meniscectomy (ACLT+MMx) of a single joint of Wistar rats. The progression of OA was verified, as shown by the microscopic deterioration of cartilage and the increasing cartilage degeneration scoring from 4 to 12 weeks postsurgery. The concentration of serological biomarkers was measured at two timepoints, along with the complete blood count and bone electrolytes, with biochemical analysis further conducted. The panel evaluated inflammatory biomarkers, bone/cartilage biomarkers, and lipid metabolic pathway biomarkers. In chronic OA rats, we found a significant reduction of total vitamin D3 and C-telopeptide fragments of type II (CTX-II) levels in the serum as compared to sham-operated rats. In contrast, the serological levels of adiponectin, leptin, and matrix metallopeptidase (MMP3) were significantly enhanced in chronic OA rats. The inflammatory markers, blood cell composition, and biochemical profile remained unchanged after surgery. In conclusion, we found that a preclinical model of single-joint OA with significant deterioration of the cartilage can lead to serological changes to the cartilage and metabolic-related biomarkers without alteration of the systemic blood and biochemical profile. Thus, this biomarker profile provides a new tool for diagnostic/therapeutic assessment in OA scientific research.

Objective: To identify and validate circulating micro RNAs (miRNAs) that mark gene expression changes in articular cartilage early in osteoarthritis (OA) pathophysiology process., Methods: Within the ongoing RAAK study, human preserved OA cartilage and plasma ( N = 22 paired samples) was collected for RNA sequencing (respectively mRNA and miRNA). Spearman correlation was determined for 114 cartilage genes consistently and significantly differentially expressed early in osteoarthritis and 384 plasma miRNAs. Subsequently, the minimal number of circulating miRNAs serving to discriminate between progressors and non-progressors was assessed by regression analysis and area under receiver operating curves (AUC) was calculated with progression data and plasma miRNA sequencing from the GARP study ( N = 71)., Results: We identified strong correlations (ρ ≥ |0.7|) among expression levels of 34 unique plasma miRNAs and 21 genes, including 4 genes that correlated with multiple miRNAs. The strongest correlation was between let-7d-5p and EGFLAM (ρ = -0.75, P = 6.9 × 10 -5 ). Regression analysis of the 34 miRNAs resulted in a set of 7 miRNAs that, when applied to the GARP study, demonstrated clinically relevant predictive value with AUC > 0.8 for OA progression over 2 years and near-clinical value for progression over 5 years- (AUC = 0.8)., Conclusions: We show that plasma miRNAs levels reflect gene expression levels in cartilage and can be exploited to represent ongoing pathophysiological processes in articular cartilage. We advocate that identified signature of 7 plasma miRNAs can contribute to direct further studies toward early biomarkers predictive for progression of osteoarthritis over 2 and 5 years.

Objective: Serum parathyroid hormone (PTH) and 25-hydroxyvitamin D [25(OH)D] have been demonstrated to be associated with pathogenesis and progression of osteoarthritis (OA). This study aimed to determine the potential causal relationship between serum PTH and 25(OH)D levels and risk of OA., Design: We applied the two-sample Mendelian randomization (MR) approach to estimate the causal roles of serum PTH and 25(OH)D on OA. The instrumental variables for serum PTH and 25(OH)D were derived from two large genome-wide association studies (GWAS), which included 29,155 and 79,366 individuals, respectively. Summary-level data for overall, hip and knee OA were extracted from a GWAS meta-analysis, including 455,221 individuals. All participants included in this study were from the European population., Results: An inverse association was observed between serum PTH levels and risk of OA (random-effects: Effect = 0.71; 95% CI: 0.54 to 0.92; fixed-effects: Effect = 0.71; 95% CI: 0.61 to 0.82). Stratified by site, serum PTH levels were found to be inversely associated with knee OA (random-effects: Effect = 0.53; 95% CI: 0.41 to 0.68; fixed-effects: Effect = 0.53; 95% CI: 0.41 to 0.68). However, there was no evidence of the causal effect of serum 25(OH)D levels on OA., Conclusions: The present study indicates an inverse causal relationship between serum PTH concentrations and development of OA. Moreover, a site-specific association was also observed between serum PTH levels and knee OA. The potential mechanisms by which serum PTH affects OA need to be further investigated., (Copyright © 2021. Published by Elsevier Ltd.)

Background/objective: Cytokines and chemokines (cytokines) are central to rheumatoid arthritis (RA) pathogenesis, with increasing use of multiplex immunoassays in clinical/research settings. Rheumatoid factor (RF) may interfere with assay outcomes by nonspecifically binding detection analytes. We evaluated the performance of a commercially available multiplex platform, including assessment of the impact of RF depletion., Methods: Forty-five cytokines were tested using Meso Scale Discovery V-PLEX™ and samples from 40 RA and 40 osteoarthritis (OA) patients. Select samples were depleted of RF using a commercial binder. Performance was assessed using intra-assay coefficients of variation (CV), intraclass correlation coefficients (ICC), percent change following RF depletion, and disease discrimination. Values above or below quantification thresholds were imputed., Results: Of the 45 cytokines analyzed, 31 yielded CVs <10%; none demonstrated CVs >30%. ICCs universally exceeded 0.85 with the exception of eight analytes. RF depletion altered cytokine values by <15% for 40 analytes with larger changes (>30%) only seen for one analyte. Twenty-three cytokines differed significantly based on measurement in plasma vs. serum. Three analytes were higher in the serum of RA vs. OA (IL-10, IP-10, TNFα), and none were significantly greater in OA vs. RA. Seventeen analytes required imputation for >50% of the samples tested, primarily related to concentrations below the lower limit of quantification threshold., Conclusion: The results from this commercially available multiplex assay were generally highly reproducible and interference induced by RF only meaningfully impacted the quantification of five of the analytes examined., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Osteoarthritis (OA) and rheumatoid arthritis (RA) are both debilitating diseases that cause significant morbidity and disability globally. This study aims to investigate the causal effects of varying blood levels of five minerals -- iron, zinc, copper, calcium, and magnesium, on OA and RA., Design: We performed two-sample Mendelian randomization (MR) analyses to assess the associations of five circulating minerals with OA and RA. Single nucleotide polymorphisms (SNPs) serving as genetic instruments for the circulating mineral levels were selected from large genome-wide association studies of European-descent individuals. The associations of these SNPs with OA and RA were evaluated in UK Biobank participants. Multiple sensitivity analyses were applied to detect and correct for the presence of pleiotropy., Results: Genetically determined copper and zinc status were associated with OA, but not with RA. Per standard deviation (SD) increment in copper increases the risk of OA (OR = 1.07, 95% CI: 1.02-1.13) and one of its subtypes, localized OA (OR = 1.08, 95% CI: 1.03-1.15). Per SD increment in zinc is positively associated with risks of OA (OR = 1.07, 95% CI: 1.01-1.13), generalized OA (OR = 1.18, 95% CI: 1.05-1.31), and unspecified OA (OR = 1.21, 95% CI: 1.11-1.31). Additionally, per SD increment in calcium decreases the risk of localized OA (OR = 0.83, 95% CI: 0.69-0.98)., Conclusions: Genetically high zinc and copper status were positively associated with OA, but not with RA. Given the modifiable nature of circulating mineral status, these findings warrant further investigation for OA prevention strategies., Competing Interests: Declaration of competing interest The authors have declared that no competing interests exist., (Copyright © 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: Circular RNA (circRNA) has been shown to affect the pathological process of osteoarthritis (OA) and is expected to become a potential marker for disease diagnosis. This study aimed to investigate the association between circRNA derived from the gene of runt-related transcription factor 2 (RUNX2) and OA risk., Methods: The expression profile of RUNX2-derived circRNAs in serum of OA patients was detected. Then, the cytological localization of screened differential circRNAs was studied. Luciferase (LUC) reporter assay was used to identify the microRNA (miRNA) sponge capacity of the circRNAs. Bioinformatics analysis was used to construct the functional pathway of this circRNA-miRNAs network. And then, the diagnostic value of RUNX2-derived circRNAs in OA was evaluated., Results: RUNX2-derived hsa&#95;circ&#95;0005526 (circ&#95;RUNX2) is significantly highly expressed in OA serum and mainly located in the cytoplasm within the cartilage cell by sponging multiple miRNAs (miR-498, miR-924, miR-361-3p, and miR-665). Bioinformatics analysis showed ECM-receptor interaction pathway ranked the most significant pathway of circ&#95;RUNX2-miRNAs regulatory network in KEGG database. The ROC curve showed that there may be good diagnostic value of serum circ&#95;RUNX2 in OA., Conclusion: RUNX2-derived circ&#95;RUNX2 may be involved in OA development via ECM-receptor interaction pathways and may be used as potential clinical indicator of OA., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

This study was conducted to investigate the β-carotene status in osteoarthritis (OA) patients and examine its relationships with the risk of inflammation and metabolic syndrome. OA patients were stratified by obesity based on body fat percentage (obese OA, n = 44; non-obese OA, n = 56), and sixty-nine subjects without OA or obesity were assigned as a non-obese control group. β-carotene, metabolic parameters, and inflammation status were assessed. Obese OA patients exhibited a significantly higher rate of metabolic syndrome ( p = 0.02), abdominal obesity ( p < 0.01), and lower β-carotene status ( p < 0.01) compared with non-obese OA and non-obese controls. After adjusting for potential confounders, β-carotene status (≥0.8 µM) was significantly inversely correlated with the risk of metabolic syndrome (odds ratio = 0.27, p < 0.01), abdominal obesity (odds ratio = 0.33, p < 0.01), high blood pressure (odds ratio = 0.35, p < 0.01), hyperglycemia (odds ratio = 0.45, p < 0.05), and inflammation (odds ratio = 0.30, p = 0.01). Additionally, subjects who had a high β-carotene status with a low proportion of metabolic syndrome when they had a low-grade inflammatory status ( p < 0.01). Obese OA patients suffered from a higher prevalence of metabolic syndrome and lower β-carotene status compared to the non-obese controls. A better β-carotene status (≥0.8 µM) was inversely associated with the risk of metabolic syndrome and inflammation, so we suggest that β-carotene status could be a predictor of the risk of metabolic syndrome and inflammation in patients with and without OA.

Osteoarthritis (OA) is the most prevalent joint disease and is one of the major causes of disability in the world. There has been an increase in the incidence of OA, which is associated with an aging population, sedentary lifestyle, and reduced physical activity. Due to the complex OA pathogenesis, there are limited diagnostic tools. OA is a degenerative joint disorder with a recognized inflammatory component, usually described as abnormal expression of inflammatory factors. For instance, interleukin 6 (IL-6) has been shown to be upregulated in serum and synovial fluid among patients with OA. Most of the inflammatory factors have been associated with the expression of long noncoding RNAs (lncRNAs). However, the role of the novel lncRNA Fer-1-like protein 4 (FER1L4) in OA is yet to be determined. Here, we interrogated the expression profile of FER1L4 in patients with OA to define its potential application as a diagnostic marker. We collected synovial fluid and blood samples from both OA cases and normal controls. Using qRT-PCR, we evaluated the expression of FER1L4 in plasma and synovial fluid. On the other hand, the expression of IL-6 in plasma and synovial fluid was assessed using ELISA. Besides, the effect of age, gender or disease stage in the expression of the FER1L4 in plasma was also estimated. Moreover, the receiver operating characteristic (ROC) curves were used to determine the impact of FER1L4 in OA cases compared with the normal controls. In addition, we analyzed the correlation between FER1L4 and IL-6 through Pearson correlation analysis. Also, IL-6 expression in overexpressed FER1L4 samples was detected in chondrocytes through western blot analysis, while FER1L4 expression following endogenous IL-6 exposure was detected by qRT-PCR. Our data showed that whereas lncRNA FER1L4 is downregulated in OA patients, IL-6 is upregulated. The plasma FER1L4 levels among the OA cases were suppressed with disease progression and old age, and the down-regulation could efficiently discriminate OA patients from normal subjects. In addition, upregulation of FER1L4 inhibited IL-6 expression in human chondrocyte cells, and treatment with different concentrations of exogenous IL-6 did not affect the expression of FER1L4. Taken together, our data demonstrates that FER1L4 could efficiently identify OA cases from normal subjects, and can also modulate the expression of IL-6 in human chondrocytes.