IL-6 secretion in osteoarthritis patients is mediated by chondrocyte-synovial fibroblast cross-talk and is enhanced by obesity

Abstract

Increasing evidence suggests that inflammation plays a central role in driving joint pathology in certain patients with osteoarthritis (OA). Since many patients with OA are obese and increased adiposity is associated with chronic inflammation, we investigated whether obese patients with hip OA exhibited differential pro-inflammatory cytokine signalling and peripheral and local lymphocyte populations, compared to normal weight hip OA patients. No differences in either peripheral blood or local lymphocyte populations were found between obese and normal-weight hip OA patients. However, synovial fibroblasts from obese OA patients were found to secrete greater amounts of the pro-inflammatory cytokine IL-6, compared to those from normal-weight patients (p < 0.05), which reflected the greater levels of IL-6 detected in the synovial fluid of the obese OA patients. Investigation into the inflammatory mechanism demonstrated that IL-6 secretion from synovial fibroblasts was induced by chondrocyte-derived IL-6. Furthermore, this IL-6 inflammatory response, mediated by chondrocyte-synovial fibroblast cross-talk, was enhanced by the obesity-related adipokine leptin. This study suggests that obesity enhances the cross-talk between chondrocytes and synovial fibroblasts via raised levels of the pro-inflammatory adipokine leptin, leading to greater production of IL-6 in OA patients.

Regulation of the Inflammatory Synovial Fibroblast Phenotype by Metastasis‐Associated Lung Adenocarcinoma Transcript 1 Long Noncoding RNA in Obese Patients With Osteoarthritis

“…Comparison between synovial fibroblasts from obese OA patients and synovial fibroblasts from normal‐weight OA patients identified a total of 19 differentially expressed lncRNAs (Supplementary Table 6 [ http://onlinelibrary.wiley.com/doi/10.1002/art.41158/abstract]). Again, this included both antisense and lincRNAs, of which the majority were lincRNAs . We observed that 9 lincRNAs were up‐regulated and 6 were down‐regulated in obese OA patient fibroblasts compared to normal‐weight OA patient fibroblasts (Figures A and B).…”

“…Synovial membrane was diced (~1 mm 3 ) and cultured in growth medium (RPMI 1640 containing 10% fetal calf serum [FCS], 1% penicillin–streptomycin, 5% l ‐glutamine, 5% sodium pyruvate, and 5% nonessential amino acids [Sigma‐Aldrich]). Synovial fibroblasts were grown to 70‐80% confluence, and phenotype was confirmed by identification of CD55‐positive cells, as described previously .…”

“…Synovial fibroblasts were grown to 70-80% confluence, and phenotype was confirmed by identification of CD55-positive cells, as described previously (15).…”

Adipokines and inflammation: is it a question of weight?

“…Our group has demonstrated that leptin, in synergy with IL‐1β, induces the expression of pro‐inflammatory factors, including NOS2, COX‐2, PGE 2 , IL‐6 and IL‐8 (CXCL8) in chondrocytes (Gomez et al ., ). Chondrocyte‐synovial fibroblast crosstalk mediates leptin‐induced IL‐6 production in OA patients (Pearson et al ., ). Moreover, leptin modulates the production of inflammatory mediators (IL‐6, IL‐8 and CCL3) by CD4+ T cells in OA patients, but not in healthy subjects (Scotece et al ., ) hence demonstrating new insights into the action of leptin in the immune system and OA pathophysiology.…”

Primary culture of mouse adipose and fibrous synovial fibroblasts under normoxic and hypoxic conditions

“…In RA, synovial fibroblast invasion causes destruction of cartilage and bone (16,21). Recent studies have in-dicated that the synovial fibroblast-chondrocyte interaction plays pivotal roles in joint homeostasis and OA pathology (1,2,20,24). The synovial fibroblast is also one of the potent cell sources for regenerative therapy of joints (18,26).…”