Key points are not available for this paper at this time.
Abstract Chondrocytes can shift their metabolism to oxidative phosphorylation (OxPhos) in 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. This study investigated whether enhancing OxPhos through pyruvate dehydrogenase kinase (PDK) 2 affects the metabolic flexibility of chondrocytes and cartilage degeneration in surgical model of OA. Among the PDK isoforms, PDK2 expression was increased by IL-1β in vitro, and in 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 DMM model. PDK2 deficiency partially restored OxPhos in IL-1β-treated chondrocytes, leading to an increased APT and NAD+/NADH ratio. These metabolic changes were accompanied by a decrease of reactive oxygen species (ROS) and senescence of chondrocytes, as well as the expression of MMP-13 and IL-6 following IL-1β-treatment. At the signaling level, PDK2 deficiency reduced p38 signaling and maintained AMPK activation, without affecting JNK, mTOR, AKT and NF-kB pathways. Among them, p38 MAPK signaling was critically involved in ROS production under glycolysis-dominant condition in chondrocytes. Our study provides the proof-of-concept for PDK2-mediated metabolic reprogramming towards OxPhos as a new therapeutic strategy for OA.
Han et al. (Wed,) studied this question.