Resistin Induces Chemokine and Matrix Metalloproteinase Production via CAP1 Receptor and Activation of P38-MAPK and NF-κB Signalling Pathways in Human Chondrocytes

Abstract BackgroundResistin is an adipokine also detected higher expression in serum and synovial fluid of patients with knee osteoarthritis (KOA). Resistin is known to be related closely to insulin resistance and inflammation. However, the pathogenic role of resistin in KOA remain unclear. Purpose of the study is to investigate whether resistin induces KOA by binding to functional receptor adenylyl cyclase-associated protein 1 (CAP1) and activating the p38 mitogen-activated protein kinase (p38-MAPK) and nuclear factor-κB (NF-κB) signalling pathways in human chondrocytes. MethodsWe enrolled 103 patients with radiographic KOA and 86 healthy participants as controls. The levels of resistin in serum and synovial fluid (SF) were determined via enzyme-linked immunosorbent assay (ELISA). CAP1 expression in cartilage tissues (21 samples of KOA cartilage and 10 samples of healthy hip cartilage) was measured using immunohistochemistry (IHC), quantitative real-time polymerase chain reaction ( qRT-PCR ), and western blotting assays. Effects of resistin on chondrocytes and CAP1 were evaluated via qRT-PCR and co-immunoprecipitation . The roles of CAP1, p38-MAPK, and NF-κB signalling pathways in the development of KOA were evaluated via adenovirus-mediated CAP1 short hairpin RNA, qRT-PCR, western blotting, and ELISA. ResultsExpression of resistin in serum and SF was elevated in severe radiographic KOA. CAP1 levels were higher in KOA cartilage and were positively correlated with resistin expression. Resistin promoted increased expression of CCL3, CCL4, MMP13, and ADAMTS-4 through CAP1 receptor. Resistin also directly bound to CAP1 as confirmed by co-immunoprecipitation. CAP1 knockdown in chondrocytes attenuated resistin-induced expression of CCL3, CCL4, MMP13, and ADAMTS-4 and activation of the p38-MAPK and NF-κB signalling pathways . ConclusionsOur study shows that resistin bound to CAP1 and upregulated the expression of proinflammatory cytokines and matrix-degrading enzymes via p38-MAPK and NF-κB signalling pathways in human chondrocytes.