The role of adipose secreted cytokines in driving the pathological changes in osteoarthritis

Adipose secreted cytokines are thought to contribute to pro-inflammatory state seen commonly in obese individuals, providing a potential metabolic link between obesity and osteoarthritis. The aim of this study is to further our understanding of the role of adipokines within OA by examining the serum and joint fluid adipokine expression profiles in relation to disease severity, BMI, and joint tissue turnover markers. The result of this study show that subchondral bone from overweight/obese hip OA patients exhibited reduced trabecular thickness, increased bone surface/bone volume ratio and an increase in the type I collagen α1/α2 ratio, compared to normal-weight hip OA patients. The serum concentration of resistin was higher in overweight/obese OA patients, compared to normal-weight OA patients (12740 vs 9818pg/mL respectively; p7 fold, 20-fold, 4-fold and 7-fold respectively). Visfatin significantly increased in catabolic proteases including MMP-1 (4-fold), MMP-2 (3-fold), MMP-3 (3-fold), MMP-7 (2.2-fold), MMP-8 (1.3-fold), MMP-9 (1.2-fold), MMP-10 (1.5-fold), and MMP-13 (5-fold) and localised to areas of cartilage damage. Targeted inhibition of adipokine signalling could therefore be a rewarding strategy for developing a novel therapeutic

eNAMPT Is Localised to Areas of Cartilage Damage in Patients with Hip Osteoarthritis and Promotes Cartilage Catabolism and Inflammation

From MDPI via Jisc Publications RouterHistory: accepted 2021-06-21, pub-electronic 2021-06-23Publication status: PublishedFunder: Versus Arthritis; Grant(s): 21530,21812Funder: Medical Research Council; Grant(s): MR/K00414X/1Obesity increases the risk of hip osteoarthritis (OA). Recent studies have shown that adipokine extracellular nicotinamide phosphoribosyltransferase (eNAMPT or visfatin) induces the production of IL-6 and matrix metalloproteases (MMPs) in chondrocytes, suggesting it may promote articular cartilage degradation. However, neither the functional effects of extracellular visfatin on human articular cartilage tissue, nor its expression in the joint of hip OA patients of varying BMI, have been reported. Hip OA joint tissues were collected from patients undergoing joint replacement surgery. Cartilage explants were stimulated with recombinant human visfatin. Pro-inflammatory cytokines and MMPs were measured by ELISA and Luminex. Localisation of visfatin expression in cartilage tissue was determined by immunohistochemistry. Cartilage matrix degradation was determined by quantifying proteoglycan release. Expression of visfatin was elevated in the synovial tissue of hip OA patients who were obese, and was co-localised with MMP-13 in areas of cartilage damage. Visfatin promoted the degradation of hip OA cartilage proteoglycan and induced the production of pro-inflammatory cytokines (IL-6, MCP-1, CCL20, and CCL4) and MMPs. The elevated expression of visfatin in the obese hip OA joint, and its functional effects on hip cartilage tissue, suggests it plays a central role in the loss of cartilage integrity in obese patients with hip OA

Resistin promotes the abnormal Type I collagen phenotype of subchondral bone in obese patients with end stage hip osteoarthritis

AbstractThe purpose of this study was to determine the effect of adiposity on the architecture and composition of hip OA subchondral bone, and to examine the pathological role of adipokines. Femoral heads were collected from normal-weight or over-weight/obese patients with hip OA. Structural parameters of subchondral bone were determined by MicroCT and type I collagen α1/α2 ratio was determined by SDS PAGE and by qRT-PCR in ex-vivo bone explants. The serum concentration of adipokines was determined by Luminex. The effect of resistin on primary OA osteoblasts was determined by analysis of Wnt pathway signal transduction, bone nodule formation, and osteoblast metabolic activity. Subchondral bone from over-weight/obese hip OA patients exhibited reduced trabecular thickness, increased bone surface/bone volume ratio, and an increase in the Type I collagen α1/α2, compared to normal-weight hip OA patients. The serum concentration of resistin was higher in overweight/obese OA patients, compared to normal-weight OA patients. Stimulation of normal-weight bone explant with recombinant resistin increased the Type I collagen α1/α2 ratio. Stimulation of primary OA osteoblasts with recombinant resistin increased Wnt signalling activation, osteoblast metabolic activity, and bone nodule formation. Increased adiposity in hip OA patients is associated with altered subchondral bone architecture and type I collagen composition.</jats:p

Long Intergenic Noncoding RNAs Mediate the Human Chondrocyte Inflammatory Response and Are Differentially Expressed in Osteoarthritis Cartilage

Objective To identify long noncoding RNAs (lncRNAs), including long intergenic noncoding RNAs (lincRNAs), antisense RNAs, and pseudogenes, associated with the inflammatory response in human primary osteoarthritis (OA) chondrocytes and to explore their expression and function in OA. Methods OA cartilage was obtained from patients with hip or knee OA following joint replacement surgery. Non-OA cartilage was obtained from postmortem donors and patients with fracture of the neck of the femur. Primary OA chondrocytes were isolated by collagenase digestion. LncRNA expression analysis was performed by RNA sequencing (RNAseq) and quantitative reverse transcriptase-polymerase chain reaction. Modulation of lncRNA chondrocyte expression was achieved using LNA longRNA GapmeRs (Exiqon). Cytokine production was measured with Luminex. Results RNAseq identified 983 lncRNAs in primary human hip OA chondrocytes, 183 of which had not previously been identified. Following interleukin-1β (IL-1β) stimulation, we identified 125 lincRNAs that were differentially expressed. The lincRNA p50-associated cyclooxygenase 2-extragenic RNA (PACER) and 2 novel chondrocyte inflammation-associated lincRNAs (CILinc01 and CILinc02) were differentially expressed in both knee and hip OA cartilage compared to non-OA cartilage. In primary OA chondrocytes, these lincRNAs were rapidly and transiently induced in response to multiple proinflammatory cytokines. Knockdown of CILinc01 and CILinc02 expression in human chondrocytes significantly enhanced the IL-1-stimulated secretion of proinflammatory cytokines. Conclusion The inflammatory response in human OA chondrocytes is associated with widespread changes in the profile of lncRNAs, including PACER, CILinc01, and CILinc02. Differential expression of CILinc01 and CIinc02 in hip and knee OA cartilage, and their role in modulating cytokine production during the chondrocyte inflammatory response, suggest that they may play an important role in mediating inflammation-driven cartilage degeneration in OA