Abstract
Compromised autophagy and mitochondrial dysfunction downregulate chondrocytic activity, accelerating the development of osteoarthritis (OA). Irisin, a cleaved form of fibronectin type III domain containing 5 (FNDC5), regulates bone turnover and muscle homeostasis. Little is known about the effect of Irisin on chondrocytes and the development of osteoarthritis. This study revealed that human osteoarthritic articular chondrocytes express decreased level of FNDC5 and autophagosome marker LC3-II but upregulated levels of oxidative DNA damage marker 8-hydroxydeoxyguanosine (8-OHdG) and apoptosis. Intra-articular administration of Irisin further alleviated symptoms of medial meniscus destabilization, like cartilage erosion and synovitis, while improved the gait profiles of the injured legs. Irisin treatment upregulated autophagy, 8-OHdG and apoptosis in chondrocytes of the injured cartilage. In vitro, Irisin improved IL-1β-mediated growth inhibition, loss of specific cartilage markers and glycosaminoglycan production by chondrocytes. Irisin also reversed Sirt3 and UCP-1 pathways, thereby improving mitochondrial membrane potential, ATP production, and catalase to attenuated IL-1β-mediated reactive oxygen radical production, mitochondrial fusion, mitophagy, and autophagosome formation. Taken together, FNDC5 loss in chondrocytes is correlated with human knee OA. Irisin repressed inflammation-mediated oxidative stress and extracellular matrix underproduction through retaining mitochondrial biogenesis, dynamics and autophagic program. Our analyses shed new light on the chondroprotective actions of this myokine, and highlight the remedial effects of Irisin on OA development.
Highlights
Articular cartilage erosion, together with synovitis and subchondral bone deterioration, are prominent features of knee osteoarthritis (OA) [1]
We examined whether fibronectin type III domain containing 5 (FNDC5) signaling was changed in articular chondrocytes in human knee
This study discovered that gains in Irisin signaling reversed autophagic influx together with autophagosome formation, compromising apoptosis to maintain survival and extracellular matrix (ECM) production in the inflamed chondrocytes
Summary
Together with synovitis and subchondral bone deterioration, are prominent features of knee osteoarthritis (OA) [1]. Chondrocyte dysfunction, like survival loss [3], extracellular matrix (ECM) underproduction [4] and proteinase overactivation [5], accelerates the cartilage degradation that deteriorates articular microstructure integrity during OA development. Biomechanical disuse and aging increase interleukin (IL)-1, IL-6 and tumor necrosis factor-alpha (TNF-α) production, and escalate oxidative stress, which dysregulates genetic and epigenetic pathways to repress chondrocytic activity and cartilage homeostasis in the OA microenvironment [6]. The loss of mitochondrial biogenesis and dynamics increases chondrocyte apoptosis [7]. Dysfunctional mitochondria result in reactive oxidative radicals overproduction, inducing oxidative damages to protein and DNA stability to hinder ECM anabolism in chondrocytes [8]
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