Myokine irisin curtails chondrocyte dysfunction and osteoarthritis through repressing WNT3A signaling

Abstract

Purpose: Loss of chondrocytic activity, like repressed survival and extracellular matrix (ECM) underproduction, escalating articular cartilage damage in the development of osteoarthritis (OA). Moderate physical exercise is known to reduce the risk of OA of the knee. Myokine Irisin, a soluble and cleaved form of fibronectin type III domain containing 5 (FNDC5), is increased upon regular exercise regular and physical workout, regulating muscle strength, energy metabolism, skeletal homeostasis, and inflammation. Little is understood about whether this myokine changed ECM metabolism or cartilage integrity in OA joints remains uncertain. This study is aimed to investigate the Irisin action to chondrocyte survival and OA development. Methods: Articular cartilage specimens were harvested from patients with end-stage knee OA who required total knee arthroplasty and patients with femoral neck fracture who required total hip replacement. Knee joints in mice overexpressing FNDC5 were subjected to destabilized medial meniscus (DMM)-induced OA. Injured knees were intra-articularly injected with Irisin recombinant proteins. Articular cartilage integrity was quantified using OARSI scoring system. Osteophyte formation was probed using μCT scanning. Irisin, matrix metalloproteinases (MMPs), inflammatory cytokine and Wnt3a expression were probed with RT-quantitative PCR and immunohistochemistry. Results: Chondrocyte in human end-stage knee OA cartilage displayed weak FNDC5 immunostaining along with strong cell apoptosis marker TUNEL staining as compared to the non-OA group. Mice overexpressing FNDC5 showed mild OA signs, like cartilage degradation, adipose oveproduction, synovial hypercellularity, swelling and osteophyte formation in experimental OA models, along with improved gait profile of the injured legs. Likewise, intra-articular injection of Irisin recombinant protein downregulated chondrocyte apoptosis and cartilage matrix loss, as well as improved articular integrity and walking patterns of injured knees. In vitro, Irisin recombinant proteins attenuated MMP3, MMP9, IL-6 expression and apoptosis, whereas autophagy program and ECM proteoglycan production were preserved in inflamed chondrocytes. The IL-1β-augmented Wnt3a signaling was downregulated upon Irisin treatment. Conclusions: FNDC5 and Irisin losses are correlated with the development of human end-stage knee OA. The myokine maintains chondrocyte survival and ECM synthesis through repressing chondrocyte inhibitory factor Wnt3a to control autophagic and apoptotic programs. This study sheds new light onto the protective action of Irisin to chondrocyte function and articular integrity in the development of OA. Profound analysis also provides the prospective of therapeutic potential of Irisin recombinant protein for slowing down knee OA development.