Abstract
Cartilage loss is a central event in the pathogenesis of osteoarthritis (OA), though other than mechanical loading, the biochemical mechanisms underlying OA pathology remain poorly elucidated. We investigated the role of Pink1-mediated mitophagy in mitochondrial fission, a crucial process in OA pathogenesis. We used a monosodium iodoacetate (MIA)-induced rodent model of OA, which inhibits the activity of articular chondrocytes, leading to disruption of glycolytic energy metabolism and eventual cell death. The OA rat cartilage exhibits significant induction of autophagy-related proteins LC3B and p62, similar to human osteoarthritic cartilage. Moreover, expression of Pink1 and Parkin proteins were also increased in OA. Here, we confirm that Pink1-mediated mitophagy leads to cell death in chondrocytes following MIA treatment, while deficiency in Pink1 expression was associated with decreased cartilage damage and pain behaviors in MIA-induced OA. Finally, we found that autophagy and mitophagy-related genes are highly expressed in human osteoarthritic cartilage. These results indicate that OA is a degenerative condition associated with mitophagy, and suggest that targeting the Pink1 pathway may provide a therapeutic avenue for OA treatment.
Highlights
Osteoarthritis (OA) is a complex disease involving the whole synovial joint tissue
One of the initial events in mitophagy is the differentiation between damaged and normal mitochondria. Following their identification by PTEN-induced kinase 1 (Pink1), defective mitochondria are engulfed in double-membraned auto-phagosomes that fuse with lysosomes, thereby merging their contents and allowing hydrolytic degradation [11]
As a proof-of-concept, we injected monosodium iodoacetate (MIA) into the knees of rats to assess the level of autophagy induction in a toxin-induced OA animal model
Summary
Osteoarthritis (OA) is a complex disease involving the whole synovial joint tissue. OA is the most common form of arthritis, characterized by cartilage destruction, as well as synovial inflammation and subchondral bone remodeling [1,2]. Among the various OA induction methods, chemically-induced OA models primarily involve the injection of toxic or inflammatory compounds directly into the knee joint to elicit intra-articular inflammation, direct matrix damage, or chondrocyte toxicity [3]. Monosodium iodoacetate (MIA), quinolone, and collagenase are among the most common chemicals used to induce OA in animals Their ease of induction is advantageous for designing reproducible studies. It was initially found that mitochondria are selectively engulfed by auto-phagosomes following a loss in membrane potential [10], suggesting that mitophagic processes regulate the selective removal of damaged mitochondria. One of the initial events in mitophagy is the differentiation between damaged and normal mitochondria Following their identification by PTEN-induced kinase 1 (Pink1), defective mitochondria are engulfed in double-membraned auto-phagosomes that fuse with lysosomes, thereby merging their contents and allowing hydrolytic degradation [11]. We sought to investigate the role of mitophagy and Pink expression in cartilage damage in OA
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