Osteoarthritis patients exhibit an autonomic dysfunction with indirect sympathetic dominance.

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.

Evaluation of circulating microRNA signature in patients with erosive hand osteoarthritis: The HOAmiR study.

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.

Circulating cytokines levels and osteoarthritis: A Mendelian randomization study.

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.

The effect of plasma cytokines on the expression of adiponectin and its receptors in the synovial membrane of joints and the infrapatellar fat pad in patients with rheumatoid arthritis and osteoarthritis.

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-1ß, 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-1ß, 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-1ß. 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.

Identification of autoantibodies against PsoP27 in synovial fluid derived from psoriatic arthritis and rheumatoid arthritis patients.

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.

Association of serum calcium, vitamin D, and C-reactive protein with all-cause and cause-specific mortality in an osteoarthritis population in the UK: a prospective cohort study.

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.

Systemic inflammatory biomarkers are novel predictors of all-cause and cardiovascular mortality in individuals with osteoarthritis: a prospective cohort study using data from the NHANES.

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.

Lipocalin-2 Serum Levels in Rheumatoid Arthritis Patients Treated with Adalimumab and Its Correlation with Proinflammatory Factors.

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-1ß, 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.

Efficacy analysis of clinical serological indicators in the diagnosis of postoperative periprosthetic joint infection in patients with rheumatoid arthritis or osteoarthritis.

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.

The Role of Adipokines between Genders in the Pathogenesis of Osteoarthritis.

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.

Metformin effects on plasma zonulin levels correlate with enhanced physical performance in osteoarthritis patients with diabetes.

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.

The effect of ferritin levels on distal femoral cartilage thickness in patients with beta thalassaemia major.

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.

Osteoarthritis in year 2021: biochemical markers.

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.

Genetically predicted circulating levels of copper and zinc are associated with osteoarthritis but not with rheumatoid arthritis.

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.

Auto-antibodies to post-translationally modified proteins in osteoarthritis.

OBJECTIVE: Autoantibodies (AutoAbs) have been observed in osteoarthritis (OA) with broad antigenicity, although their prevalence and role remain unclear. Post-translational modification (PTMs) of proteins (oxidation, carbamylation, citrullination) is associated with synovitis and can lead to AutoAb development. Given the prevalence of synovitis, we explored whether AutoAbs to PTM-antigens are common in OA compared with rheumatoid arthritis (RA). METHODS: Serum (n = 895) was obtained from healthy controls, OA and RA patients; and arthritic synovial fluid (SF, n = 290). ELISAs were used to quantify anti-citrullinated peptide (ACPA), anti-carbamylated protein (anti-CarP), anti-oxidized collagen (anti-ROS-CI/CII) antibodies. RESULTS: In sera, positivity for PTM-antigens AutoAbs was observed at a lower frequency in OA with 64.1% (95%CI: 57.2-70.1%) more ACPA+ and 29.8% (21.0-37.3%) more anti-CarP + patients in RA (both P < 0.0001). Levels of ACPA, anti-CarP were also lower in OA (P < 0.0001). Anti-ROS-CII positivity was lower in OA compared to RA (16.6%, 4.8-28.6%) less frequent, P = 0.033) but not anti-native-CII. There was no impact of age/gender on AutoAbs associations with diseases either looking at positivity or levels. In SF, OA patients were often ACPA+ (45.9%) although less frequently than in RA (P = 0.004). Anti-CarP were rarely observed (<5% all samples). All collagen AutoAbs were more frequent in RA compared to OA (all P < 0.010) but only levels of anti-CII and anti-ROS-CII were significantly higher in they RA (P < 0.050). CONCLUSION: Although the frequency of AutoAbs for PTM proteins were lower in OA sera compared to RA, a higher proportion of OA SF were positive. The relative retention of AutoAbs in the OA joint requires further investigation.

A Mendelian randomization study on the role of serum parathyroid hormone and 25-hydroxyvitamin D in osteoarthritis.

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.

Causal relationship of serum nutritional factors with osteoarthritis: a Mendelian randomization study.

OBJECTIVES: OA is the most common form of arthritis worldwide and has a major impact on the quality of life among the older population. This study aimed at determining the potential causal effects of several serum nutritional factors on OA. METHODS: A total of seven serum nutritional factors were identified from genome-wide association studies. Summary statistics for OA were obtained from UK Biobank (194 153 for women and 166 988 for men) and a large genome-wide association studies meta-analysis based on the European population (455 221, 393 873 and 403 124 for overall, hip and knee OA, respectively). Two-sample Mendelian randomization approach was used to estimate the causal association between the selected nutritional factors and the risk of OA. RESULTS: The Mendelian randomization analyses suggested that serum calcium levels were inversely associated with overall OA (95% CI, 0.595, 0.850), hip OA (95% CI, 0.352, 0.799) and knee OA (95% CI, 0.461, 0.901). Serum retinol levels were also inversely associated with hip OA (95% CI, 0.257, 0.778). Moreover, sex-specific associations were observed between serum calcium levels (95% CI, 0.936, 0.998), iron levels (95% CI, 1.000, 1.012), selenium levels (95% CI, 0.923, 0.999) and OA in women. CONCLUSION: In this study, an inverse causal association between serum calcium levels and OA was established. Serum retinol levels were inversely associated with hip OA. In addition, we provide evidence for the causal effect of serum calcium, iron and selenium on the risk of OA in women.

Inhibition of hepatocyte growth factor/c-Met signalling abrogates joint destruction by suppressing monocyte migration in rheumatoid arthritis.

OBJECTIVES: To determine the expression of hepatocyte growth factor (HGF) in RA biological fluids, the role of HGF in monocyte migration and the therapeutic effect of the c-Met inhibitor savolitinib in an arthritis model mice. METHODS: HGF/c-Met expression in serum, SF and synovial tissues (STs) obtained from RA patients and controls, as well as RA fibroblast-like synoviocytes (FLSs), was evaluated by ELISA and immunostaining. To determine the function of HGF in RA SF, we preincubated RA SF with a neutralizing anti-HGF antibody and measured the chemotactic ability of a human acute monocytic leukaemia cell line (THP-1). Additionally, examinations were conducted of SKG mice treated with savolitinib for 4 weeks. RESULTS: HGF levels in serum from RA patients were significantly higher than those in the controls and were decreased by drug treatment for 24 weeks. Additionally, the HGF level in SF from RA patients was higher than that in SF from OA patients. HGF and c-Met expression was also noted in RA STs. Stimulation of RA FLSs with TNF-α increased HGF/c-Met expression in a concentration-dependent manner, and c-Met signal inhibition suppressed production of fractalkine/CX3CL1 and macrophage inflammatory protein-1α/CCL3. When HGF was removed by immunoprecipitation, migration of THP-1 in RA SF was suppressed. In SKG mice, savolitinib significantly suppressed ankle bone destruction on µCT, with an associated reduction in the number of tartrate-resistant acid phosphatase-positive osteoclasts. CONCLUSION: HGF produced by inflammation in synovium of RA patients activates monocyte migration to synovium and promotes bone destruction via a chemotactic effect and enhanced chemokine production.

Potential emerging roles of the novel adipokines adipolin/CTRP12 and meteorin-like/METRNL in obesity-osteoarthritis interplay.

BACKGROUND: Several insights into obesity-osteoarthritis (OA) relationship have been recently highlighted. Adipolin and metrnl are new adipokines also secreted by chondrocytes. However, their role in OA, and obesity-OA interplay hasn't been elucidated. Therefore, this study was designed to investigate the circulating as well as synovial fluid (SF) levels of adipolin and metrnl in osteoarthritic-patients compared to non-osteoarthritic subjects, and to study their association with OA-severity, dyslipidemia and insulin resistance (IR). METHODS: Patients with osteoarthritis and obesity (n = 30), and subjects with obesity not suffering OA (n = 25) were enrolled in the current study. Circulating and SF-levels of adipolin, metrnl, and insulin, as well as SF-levels of matrix-metalloproteinase-13 (MMP-13) were measured by ELISA. Knee-radiographs using X-ray were done to determine OA-severity, and investigate its association with adipokines' levels. RESULTS: Serum and SF-adipolin levels showed tendency to be lower in OA-patients compared to non-OA-subjects; serum: 0.64 [0.45-0.85] and 0.73 [0.62-0.78] ng/ml, p = 0.174, and SF: 0.53 [0.34-0.69] and 0.63 [0.44-0.74] ng/ml, p = 0.353, respectively. Additionally, serum adipolin showed negative-association with SF-MMP-13. However, when stratifying OA-patients into various severity grades, serum adipolin levels did not show a significant difference between them. Regarding serum metrnl, it was significantly lower in OA-patients compared to non-OA-subjects; 19.68 [10.40-53.40] and 48.83 [20.80-86.60] pg/ml, respectively, p = 0.018. Surprisingly, SF-metrnl levels were higher in OA-patients compared to non-OA-subjects; 912 [367-1524] and 315 [125-484] pg/ml, respectively, p = 0.007. SF-metrnl showed positive-association with insulin resistance, and negative-association with SF-MMP-13. Moreover, higher serum metrnl levels were found to be slightly associated with lower likelihood of OA in subjects with obesity; OR = 0.978, CI (0.960- 0.996), p = 0.02, and its levels were also found to be relatively lower in grade-4 compared to the less severe OAgrades. CONCLUSIONS: Metrnl, and to a lesser extent adipolin seem to be interrelated with OA. Different in-context regulatory mechanisms for metrnl production from various tissues are strongly suggested. Importantly, the findings of the current study shed lights on metrnl as a potential novel mediator and therapeutic target to consider in obesity-OA interplay.

Systematic evaluation of sample preparation strategy for GC-MS-based plasma metabolomics and its application in osteoarthritis.

Sample preparation plays a crucial part in plasma metabolomics. In order to obtain an optimal sample extraction method for gas chromatography mass spectrometry (GC-MS)-based plasma metabolomics, five different extraction strategies including protein precipitation, liquid-liquid extraction and solid-phase extraction were evaluated systematically for both plasma untargeted- and targeted-metabolomics. The comprehensive evaluation revealed that the all-in-one sample preparation method, MeOH-MTBE-H2O (1:5:1.5, v/v/v), was the optimal extraction method for both untargeted- and targeted-metabolomics. Next, the optimal sample preparation protocol was applied in plasma metabolomics of osteoarthritis (OA). A panel containing cholesterol, lactic acid, stearic acid, alpha-tocopherol and oxalic acid was selected as candidate biomarker to distinguish OA patients from healthy controls (HC) based on the support vector machine (SVM) classification model. The discriminating capability of the candidate biomarker panel was further validated successfully with logistic regression and principal components analysis (PCA) analysis. Therefore, the panel could potentially act as diagnostic biomarker for osteoarthritis.