Subgroups Of Osteoarthritis Patients Research Articles

Separating friend from foe: Inhibition of TGF-β-induced detrimental SMAD1/5/9 phosphorylation while maintaining protective SMAD2/3 signaling in OA chondrocytes

Transforming growth factor-β (TGF-β) signaling via SMAD2/3 is crucial to control cartilage homeostasis. However, TGF-β can also have detrimental effects by signaling via SMAD1/5/9 and thereby contribute to diseases like osteoarthritis (OA). In this study, we aimed to block TGF-β-induced SMAD1/5/9 signaling in primary human OA chondrocytes, while maintaining functional SMAD2/3 signaling. Human OA chondrocytes were pre-incubated with different concentrations of ALK4/5/7 kinase inhibitor SB-505124 before stimulation with TGF-β. Changes in SMAD C-terminal phosphorylation were analyzed using Western blot and response genes were measured with quantitative Polymerase Chain Reaction. To further explore the consequences of our ability to separate pathways, we investigated TGF-β-induced chondrocyte hypertrophy. Pre-incubation with 0.5µM SB-505124, maintained ±50% of C-terminal SMAD2/3 phosphorylation and induction of JUNB and SERPINE1, but blocked SMAD1/5/9-C phosphorylation and expression of ID1 and ID3. Furthermore, TGF-β, in levels comparable to those in the synovial fluid of OA patients, resulted in regulation of hypertrophic and dedifferentiation markers in OA chondrocytes; i.e. an increase in COL10, RUNX2, COL1A1, and VEGF and a decrease in ACAN expression. Interestingly, in a subgroup of OA chondrocyte donors, blocking only SMAD1/5/9 caused stronger inhibition on TGF-β-induced RUNX2 than blocking both SMAD pathways. Our findings indicate that using low dose of SB-505124 we maintained functional SMAD2/3 signaling that blocks RUNX2 expression in a subgroup of OA patients. We are the first to show that SMAD2/3 and SMAD1/5/9 pathways can be separately modulated using low and high doses of SB-505124 and thereby split TGF-β's detrimental from protective function in chondrocytes.

Efficacy and safety of colchicine for the treatment of osteoarthritis: a systematic review and meta-analysis of intervention trials

ObjectiveColchicine, an approved treatment for gout, has been trialed in many diseases including osteoarthritis (OA) due to its anti-inflammatory effects. However, its efficacy and safety remain unclear in OA. This systematic review and meta-analysis evaluated the efficacy and safety of colchicine for the treatment of OA.MethodsPubMed, Web of Science, Scopus, and Cochrane Central were searched from inception through September 2022. Two reviewers independently screened for randomized controlled trials (RCTs) comparing colchicine with placebo or other active comparators for the treatment of OA (knee, hand, or hip OA), extracted data, and performed Cochrane risk of bias assessments.ResultNine RCTs for the knee OA and one for the hand OA were identified, consisting of 847 patients (429 in colchicine arms, 409 in control arms). The studies were conducted between 2002 and 2021 with follow-up periods ranging from 2 to 12 months, in India, Iran, Turkey, Australia, Singapore, and Iraq. Moderate-quality evidence showed no clinically important pain reduction with colchicine compared to control (standardized mean difference [SMD], 0.17; 95% confidence interval [CI], − 0.55, 0.22). Moderate-quality evidence showed no improvement in function with colchicine compared to control in knee OA patients (SMD, − 0.37; 95% CI, − 0.87, 0.13). Colchicine showed an acceptable safety profile with AEs/SAEs comparable to control.ConclusionCurrent evidence does not suggest a benefit of colchicine in reducing pain and improving physical function in the overall cohort of hand/knee OA patients. Future trials should focus on the subgroups of OA patients with local or systemic inflammation and/or mineralization who might benefit from colchicine.Graphical abstractKey Points•Colchicine is an approved treatment for gout that has been trialed in many diseases including osteoarthritis (OA) due to its anti-inflammatory effects. However, the benefit and harms of colchicine in OA remain unclear.• Current evidence from randomized control trials does not suggest a benefit of colchicine in reducing pain and improving physical function for the treatment of OA patients.• Future trials of colchicine in OA should focus on the subgroups of OA patients with local or systemic inflammation and/or mineralization who might benefit from colchicine.

Metabolomic signatures for the longitudinal reduction of muscle strength over 10 years

Purpose: Osteoarthritis (OA) is the most common type of arthritis that affects about 10% of world population aged 60 years and older. OA is considered to be the major source of joint pain and disability that leads to serious socioeconomic consequences worldwide. Skeletal muscles are essential components of the neuromuscular skeletal system that have an integral role in the structure and function of synovial joints. Muscle weakness and atrophy is one of the earliest signs of ageing. Limited number of studies have been performed to investigate the implication of muscle weakness in the pathogenesis of OA, and our recent study on endotypes of OA found that a sub-group of OA patients could be classified as muscle weakness OA.

Characterizing patients' expectations in hip and knee osteoarthritis.

Previous research reported conflicting findings regarding the association of sociodemographic and clinical variables with expectations for surgical outcomes. The current study aimed to identify and characterize different subgroups of osteoarthritis patients with respect to amount and level of expectations, and to examine factors that are associated with expectations. Hip and knee patients (n = 287) completed a questionnaire 1 week post consultation. Linear regression analyses were performed to examine whether sociodemographic (e.g., age, sex) and clinical factors (e.g., pain, function) were associated with expectations. Latent class analysis (LCA) was used to identify different subgroups and the step 3 method was conducted to assess subgroup characteristics. Mean age of patients was 70 years (SD = 8) and 57% of patients was female. Most improvement was expected in walking ability and pain relief. Higher expectations were associated with younger age, male sex, and functional disability. Both hip and knee patients could be classified into three subgroups. These subgroups differed significantly on pain and other symptoms, and functional disability. Both hip and knee patients reported pain and other osteoarthritis symptoms and functional disability and consequently had high expectations in these areas for treatment outcomes. Higher expectations were characterized by more pain, more symptoms and more functional disability. These insights could guide physicians in the discussion of expectations during consultation.

Clutering analyisis and clinical data integration reveals two subgroups of osteoarthritis patients

Clutering analyisis and clinical data integration reveals two subgroups of osteoarthritis patients

IL-37 diminishes proteoglycan loss in human OA cartilage: donor-specific link between IL-37 and MMP-3

A hallmark of osteoarthritis (OA) is degradation of articular cartilage proteoglycans. In isolated human OA chondrocytes, the anti-inflammatory cytokine Interleukin-37 (IL-37) lowers the expression of the proteolytic MMP and ADAMTS enzymes, which mediate this degradation. Therefore, we investigated if IL-37 protects against proteoglycan loss in freshly obtained human OA explants. Human OA cartilage explants were incubated with IL-37. Release of sulphated proteoglycans (sGAGs) was measured with the dimethylmethylene-blue assay. Production and degradation of newly synthesized proteoglycans was measured using 35S-sulphate. Proteoglycan and proteolytic enzyme expression were analyzed by qPCR and Western Blot. Proteolytic activity was determined by measuring MMP- and ADAMTS-generated aggrecan neo-epitopes with ELISA and by using MMP-3-, MMP-13- or ADAMTS-5-inhibitors. Over time, a linear release of sGAGs from OA cartilage was measured. IL-37 reduced this release by 87μg/ml (24%) 95%CI [21.04-141.4]. IL-37 did not affect 35S-sulphate incorporation or proteoglycan gene expression. In contrast, IL-37 reduced loss of 35S-sulphate labeled GAGs and reduced MMP-3 protein expression, indicating that IL-37 inhibits proteoglycan degradation. Remarkably, we observed two groups of patients; one group in which MMP-3-inhibition lowered sGAG release, and one group in which ADAMTS5-inhibition had this effect. Remarkably, IL-37 was only functional in the group of patients that responded to MMP-3-inhibition. We identified a relationship between IL-37 and reduced sGAG loss in OA cartilage. Most likely, this effect is mediated by inhibition of MMP-3 expression. These results suggest that IL-37 could be applied as therapy in a subgroup of OA patients, in which cartilage degradation is mediated by MMP-3.

Modulation of insulin-like growth factor 1 levels in human osteoarthritic subchondral bone osteoblasts

Human osteoarthritis (OA) is characterized by cartilage loss, bone sclerosis, osteophyte formation and inflammation of the synovial membrane. We previously reported that OA osteoblasts (Ob) show abnormal phenotypic characteristics possibly responsible for bone sclerosis and that two subgroups of OA patients can be identified by low or high endogenous production of prostaglandin E 2 (PGE 2) by OA Ob. Here, we determined that the elevated PGE 2 levels in the high OA subgroup were linked with enhanced cyclooxygenase-2 (COX-2) protein levels compared to normal and low OA Ob. A linear relationship was observed between endogenous PGE 2 levels and insulin-like growth factor 1 (IGF-1) levels in OA Ob. As parathyroid hormone (PTH) and PGE 2 are known stimulators of IGF-1 production in Ob, we next evaluated their effect in OA Ob. Both subgroups increased their IGF-1 production similarly in response to PGE 2, while the high OA subgroup showed a blunted response to PTH compared to the low OA group. Conversely, only the high OA group showed a significant inhibition of IGF-1 production when PGE 2 synthesis was reduced with Naproxen, a non-steroidal antiinflammatory drug (NSAID) that inhibits cyclooxygenases (COX). The PGE 2-dependent stimulation of IGF-1 synthesis was due in part to the cAMP/protein kinase A pathway since both the direct inhibition of this pathway with H-89 and the inhibition of EP2 or EP4 receptors, linked to cAMP production, reduced IGF-1 synthesis. The production of the most abundant IGF-1 binding proteins (IGFBPs) in bone tissue, IGFBP-3, -4, and -5, was lower in OA compared to normal Ob independently of the OA group. Under basal condition, OA Ob expressed similar IGF-1 mRNA to normal Ob; however, PGE 2 stimulated IGF-1 mRNA expression more in OA than normal Ob. These data suggest that increased IGF-1 levels correlate with elevated endogenous PGE 2 levels in OA Ob and that higher IGF-1 levels in OA Ob could be important for bone sclerosis in OA.