Exercise myokine counteracts chondrocyte senescence and osteoarthritis development through mitochondrial metabolism reprogramming

Abstract

Purpose: Chondrocyte senescence accelerates apoptosis and extracellular matrix loss, accelerating articular cartilage deterioration in the development of osteoarthritis (OA). Fibronectin type III domain containing 5 (FNDC5), is an important exercise myokine to slow age-related diseases, like sarcopenia, osteoporosis, obesity, and neural degeneration, etc. Little is known about whether the molecule affect chondrocyte fate or cartilage metabolism in OA joints. This study aimed to investigate what role FNDC5 may play in chondrocyte aging and OA development in human and in mice. Methods: Osteoarthritic cartilage and non-OA cartilage in the leftover articular specimens were biopsied from patients with knee OA who required total knee replacement. FNDC5 transgenic mice were received destabilized medial meniscus (DMM) to induce OA. Articular cartilage damage, osteophyte formation, kinematics, and pain behavior of injured legs were probed using OARSI score, μCT imaging, catwalk, and von Frey filaments test. Senescence-associated β-galactosidase (SA-β-gal) activity, aging makers, and inflammatory cytokines were quantified using biochemical staining and RTPCR. Mitochondrial metabolites and biology were quantified using liquid chromatography-tandem mass spectrometry, seahorse extracellular influx, and laser confocal microscopy. Results: A plenty of SA-β-gal-stained senescent chondrocytes together with weak FNDC5 immunostaining were present in human osteoarthritic cartilage, as compared with the non-OA cartilage. FNDC5 transgenic (FNDC5Tg) mice showed thickened articular cartilage, increased chondrocytes, high subchondral bone mass, and well woven trabecular microstructure. DMM-injured knee joints displayed less OA signs, including articular cartilage erosion, synovitis, and osteophyte formation. FNDC5 overexpression compromised DMM-mediated pain score and irregular walking patterns and repressed gait profiles of injured legs. Likewise, intra-articular injection with Irisin, a soluble form of FNDC5, slowed OA development in DMM-injured legs. In vitro, FNDC5 overexpression reversed IL-1β-inhibited mitochondrial respiration, ATP production, mitochondrial fusion, and mitophagy. FNDC5 improved mitochondrial α-ketoglutarate production, a key TCA cycle metabolite, repressing senescence program (SA-β-gal activity, p16, p21 expression, and IL-6 production) and retaining ECM production in inflamed chondrocytes. Conclusions: FDNC5 loss is correlate with chondrocyte aging in the development of OA in human and in mice. The myokine sustains chondrocytic activity through sustaining mitochondrial TCA cycle metabolism and biology to protect against inflammation-induced senescence. This study shines light onto the mitochondrial mechanism underlying the chondroprotective actions of FNDC5 to articular integrity. Collective investigations also highlight the remedial effects of FNDC5 and Irisin for OA development.