Orexin A prevents degradation of the articular matrixes in human primary chondrocyte culture

Abstract

Excessive production of pro-inflammatory cytokines such as interleukin-1β (IL-1β) plays a key role in the pathophysiological development of osteoarthritis (OA). Orexin A is an important peptide of hypothalamic origin, which has displayed its multiple biological functions in several chronic diseases via activation of its specific G-protein coupled receptors, orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R). In this study, we aimed to characterize the protective effects of orexin A against IL-1β-induced degradation of articular cartilage matrixes in human chondrocytes. Our results indicate that OX1R but not OX2R was expressed in human chondrocytes. We also found that the expression of OX1R was significantly lower in chondrocytes from OA patients, and that treatment with IL-1β decreased the expression of OX1R in a dose-dependent manner. The presence of orexin A ameliorated IL-1β-induced degradation of type II collagen and aggrecan, the two major components of articular cartilage matrixes. Our results also show that orexin A prevented IL-1β-induced expression of catabolic enzymes such as MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5. Mechanistically, orexin A treatment abolished activation of the transcriptional factor NF-κB via inhibition of KKα/IκB-α phosphorylation and IκB-α degradation. These findings suggest that orexin A might act as an effective therapeutic agent for the treatment of OA.