Dimeric PKM2 in chondrocytes impairs mitochondrial homeostasis in osteoarthritis.

Abstract

Cartilage degradation is considered a hallmark of end-stage osteoarthritis (OA), characterized by significant alterations in the extracellular matrix (ECM). This study examines the role of pyruvate kinase muscle type 2 (PKM2) dimerization in cartilage degradation and ECM homeostasis in OA. Bioinformatic analyses identified an upregulation of PKM in OA cartilage, particularly within fibrocartilage subpopulations. Elevated expression and dimerization of PKM2 were observed in both human and murine OA cartilage. Chondrocyte-specific PKM2 deficiency, along with treatment using TEPP-46, a PKM2 tetramer stabilizer, reduced OA progression and promoted cartilage matrix production in a murine OA model with destabilization of the medial meniscus (DMM). Mechanistically, PKM2 deficiency or tetramer stabilization promoted mitochondrial fusion and preserved mitochondrial function via disruption of PKM2-ERK interaction, resulting in ERK-dependent upregulation of mitofusin 1 (MFN1), but not mitofusin 2 (MFN2). Notably, AAV-mediated MFN1 knockdown abrogated the chondroprotective effects of PKM2 deficiency. These findings indicate that targeting PKM2 dimerization may represent a promising therapeutic strategy for mitigating OA. Increased PKM2 dimerization in osteoarthritic cartilage plays a pivotal role in extracellular matrix (ECM) degradation during osteoarthritis progression. Stabilization of PKM2 tetramers by TEPP-46 or genetic deletion of PKM2 disrupts PKM2-ERK interaction, promotes upregulation of the mitochondrial fusion protein MFN1, preserves mitochondrial function, and restores ECM homeostasis.