Hexokinase 2 Suppression Alleviates the Catabolic Properties in Osteoarthritis via HMGA2 and Contributes to Pulsed Electromagnetic Field-mediated Cartilage Protection

Abnormalities in glycolytic pathways are prominent factors in the pathogenesis of osteoarthritis (OA). The key glycolytic enzyme Hexokinase 2 (HK2) is highly expressed in chondrocytes in OA; however, its role remains unclear. Pulsed electromagnetic field (PEMF) is commonly used for the treatment of OA. However, the role of PEMF in cartilage damage and the underlying mechanisms are not well understood. Herein, we found that HK2 suppression down-regulated catabolic pathways and alleviated inflammatory responses in OA chondrocytes, whereas HK2 overexpression stimulated inflammation and catabolic levels; moreover, inhibition of HK2 has potential anti-inflammatory and anti-catabolic properties by regulating the expression of HMGA2. PEMF dramatically inhibited the increase in glycolytic activity and catabolic metabolism level in OA and could alleviate the OA phenotype by modulating the HK2/HMGA2 signaling axis. Suppressing HK2 via adeno-associated virus (AAV) in articular cartilage demonstrated that PEMF reduces cartilage damage and OA symptoms through HK2 knockdown. Furthermore, the HK2 inhibitor Lonidamine, in combination with PEMF, more effectively ameliorated cartilage degeneration in OA. Overall, our findings improve understanding of HK2's role in OA and offer new insights for targeting HK2 in treatment. Furthermore, our results provide new clues for the reducing of catabolism and cartilage damage using PEMF.