Mouse and in vitro osteoarthritis model study demonstrating that MOTS-c attenuates OA progression by suppressing NLRP3 inflammasome-mediated pyroptosis and reducing cartilage matrix degradation through an Nrf2-dependent antioxidant mechanism, preserving chondrocyte viability under inflammatory conditions. Expands MOTS-c's therapeutic applications to joint disease. Establishes MOTS-c as a potential disease-modifying OA therapy—providing mechanistic evidence that mitochondrial peptide supplementation can interrupt the mitochondrial dysfunction → pyroptosis → cartilage degradation cascade that drives OA progression, offering a novel biological target for a disease with few effective pharmacological options.
Abstract
Osteoarthritis, a common chronic degenerative disease in the field of orthopedics, is caused by the interaction of mechanical stress, traumatic inflammation, and metabolic imbalance, and this interaction progresses over time. MOTS-c, a mitochondria-derived peptide, exerts pivotal roles in regulating metabolism, anti-inflammation, and antioxidant stress responses. However, current research on the role of MOTS-c in osteoarthritis remains scarce, and its specific mechanism of action remains unclear. Therefore, this study aims to further explore the molecular mechanisms by which MOTS-c regulates osteoarthritis. Exogenous supplementation of MOTS-c improves mitochondrial dysfunction, inhibits the activation of inflammatory bodies and rescues chondrocyte pyroptosis, thereby regulating the metabolic balance of extracellular matrix (ECM). Mechanistically, MOTS-c plays a key role in LPS-induced oxidative stress and chondrocyte pyroptosis through the Nrf2/TXNIP/NLRP3 axis. Our research demonstrates that MOTS-c can not only effectively inhibit the expression of inflammatory factors but also promote the expression of major components of the extracellular matrix (ECM) and suppress the production of matrix metalloproteinases. We validated the in vivo efficacy of MOTS-c by establishing a murine osteoarthritis model. Analysis of imaging and histopathological results revealed that MOTS-c can effectively delay the degeneration of articular cartilage and ameliorate the progression of osteoarthritis. Collectively, our findings uncover the intrinsic regulatory mechanism of MOTS-c in chondrocytes and its potential value in the treatment of osteoarthritis.