Increased oxidative phosphorylation through pyruvate dehydrogenase kinase 2 deficiency ameliorates cartilage degradation in mice with surgically induced osteoarthritis

Chondrocytes can shift their metabolism to oxidative phosphorylation (OxPhos) in the early stages of osteoarthritis (OA), but as the disease progresses, this metabolic adaptation becomes limited and eventually fails, leading to mitochondrial dysfunction and oxidative stress. Here we investigated whether enhancing OxPhos through the inhibition of pyruvate dehydrogenase kinase (PDK) 2 affects the metabolic flexibility of chondrocytes and cartilage degeneration in a surgical model of OA. Among the PDK isoforms, PDK2 expression was increased by IL-1β in vitro and in the articular cartilage of the DMM model in vivo, accompanied by an increase in phosphorylated PDH. Mice lacking PDK2 showed significant resistance to cartilage damage and reduced pain behaviors in the DMM model. PDK2 deficiency partially restored OxPhos in IL-1β-treated chondrocytes, leading to increases in APT and the NAD+/NADH ratio. These metabolic changes were accompanied by a decrease in reactive oxygen species and senescence in chondrocytes, as well as an increase in the expression of antioxidant proteins such as NRF2 and HO-1 after IL-1β treatment. At the signaling level, PDK2 deficiency reduced p38 signaling and maintained AMPK activation without affecting the JNK, mTOR, AKT and NF-κB pathways. p38 MAPK signaling was critically involved in reactive oxygen species production under glycolysis-dominant conditions in chondrocytes. Our study provides a proof of concept for PDK2-mediated metabolic reprogramming toward OxPhos as a new therapeutic strategy for OA. Osteoarthritis is a common joint disease where cartilage breaks down, causing pain and stiffness. Chondrocytes, the cells in cartilage, usually rely on glycolysis for energy production. However, in early OA, they can switch to oxidative phosphorylation as an alternative energy pathway. This study aimed to see if modulating chondrocyte metabolism could slow OA progression. Researchers focused on PDK2, a protein that inactivates PDH, thereby reducing OxPhos activity in chondrocytes. They used mice genetically modified to lack PDK2 and compared them with normal mice with surgically induced OA. They found that, without PDK2, chondrocytes had better energy balance by using OxPhos more effectively and less oxidative stress, which slowed OA progression. This suggests that targeting PDK2 could be a new way to treat OA by improving chondrocyte metabolism. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.