Inflammation-Mediated Aberrant Glucose Metabolism in Subchondral Bone Induces Osteoarthritis

• Published in: Stem cells (Dayton, Ohio) Ohio), 2023-05, Vol.41 (5), p.482-492
• Main Authors: Ying, Jun, Wang, Pinger, Shi, Zhenyu, Xu, Jianbo, Ge, Qinwen, Sun, Qi, Wang, Weidong, Li, Ju, Wu, Chengliang, Tong, Peijian, Jin, Hongting
• Format: Article
• Language: English
• Subjects: Animals; Bone and Bones - metabolism; Cartilage, Articular - pathology; Humans; Inflammation - pathology; Mice; Osteoarthritis; Osteogenesis; Sclerosis - complications; Sclerosis - metabolism; Sclerosis - pathology
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1093/stmcls/sxad012

Abstract Osteoarthritis (OA) is an entire joint disease with pathological alteration in both articular cartilage and subchondral bone. It has been recognized recently the association between metabolic syndrome and OA, particularly glucose metabolism in regulation of articular cartilage homeostasis and joint integrity. Whereas the role of glucose metabolism in subchondral bone sclerosis remains largely unknown during pathogenesis of OA. Consistent with common OA features, we observed subchondral bone sclerosis and abnormal bone remodeling in human OA joints and murine OA joints as reflected by hyperactive bone resorption and overall bone formation which was measured via dynamic histomorphometry. Osx-CreER;tdTomato mice also displayed the similar overall bone formation under injury-induced OA condition. Immunohistochemistry further revealed increased IL-1β expression in human and murine OA subchondral bone. Given the inflammatory environment in joints under OA condition, we treated MC3T3-E1 cell, a pre-osteoblast cell line, with IL-1β in this study and demonstrated that IL-1β treatment could stimulate the cell osteogenic differentiation and meanwhile upregulate glycolysis and oxidative phosphorylation in cell cultures. More importantly, intraperitoneal injection of 2-deoxy-D-glucose (2-DG) and oligomycin (OGM), respectively, suppressed the subchondral bone glycolysis and oxidative phosphorylation in mice. Consequently, 2-DG and OGM treatment attenuated abnormal osteoblast differentiation and protected against aberrant bone formation in subchondral bone and articular cartilage degradation in wildtype mice following with joint injury. Collectively, these data strongly suggest glycolysis and oxidative may serve as important therapeutic targets for OA treatment. Graphical Abstract Graphical Abstract