ABSTRACT
Osteoarthritis (OA), a prevalent degenerative joint disease, affects a substantial global population. Despite the elusive etiology of OA, recent investigations have implicated mitochondrial dysfunction as a significant factor in disease pathogenesis. Mitochondria, pivotal cellular organelles accountable for energy production, exert essential roles in cellular metabolism. Hence, mitochondrial dysfunction can exert broad-ranging effects on various cellular processes implicated in OA development. This comprehensive review aims to provide an overview of the metabolic alterations occurring in OA and elucidate the diverse mechanisms through which mitochondrial dysfunction can contribute to OA pathogenesis. These mechanisms encompass heightened oxidative stress and inflammation, perturbed chondrocyte metabolism, and compromised autophagy. Furthermore, this review will explore potential interventions targeting mitochondrial metabolism as means to impede or decelerate the progression of OA. In summary, this review offers a comprehensive understanding of the involvement of mitochondrial metabolism in OA and underscores prospective intervention strategies.
ABSTRACT
Osteoarthritis (OA) is a common age-related disorder. Chondrocytes in joint tissue play a critical role in normal articular cartilage function and tissue homeostasis. Local inflammatory cytokine-induced chondrocyte senescence contributes to the development and progression of OA. Various dipeptidyl peptidase-4 (DPP-4) inhibitors have been widely used to treat type 2 diabetes. Here, we report a novel pharmacological role of the DPP-4 inhibitor vildagliptin in chondrocyte senescence. Our data indicate that DPP-4 is an inducible factor responsive to tumor necrosis factor-α (TNF-α) treatment in chondrocytes. The inhibition of DPP-4 by vildagliptin ameliorates TNF-α-induced chondrocyte senescence as determined by cellular senescence-associated ß-galactosidase (SA-ß-Gal) activity. Vildagliptin displayed protective capabilities against TNF-α-induced chondrocyte cell cycle arrest in the G1 phase. Moreover, vildagliptin suppresses the three major TNF-α-induced chondrocyte senescence proteins including p53, p21, and plasminogen activator inhibitor-1 (PAI-1). Vildagliptin also suppresses TNF-α-induced p53 acetylation at K382. Consistently, our findings demonstrate the inhibitory effect of vildagliptin on p53 acetylation, which is mediated by sirtuin 1 (SIRT1) as the inhibition of SIRT1 negated the inhibitory action of vildagliptin on p53 acetylation. Furthermore, we found that the effect of vildagliptin on SIRT1 protection is adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) dependent, and the inhibition of AMPK activity negated the protection of vildagliptin against SIRT1 and chondrocytes senescence. In conclusion, our study explored the molecular mechanism and protective effect of the antidiabetic drug vildagliptin against chondrocyte senescence, and our findings imply that vildagliptin has a therapeutic potential in OA. © 2019 IUBMB Life, 1-2, 2019.
