Glycolysis in bone remodeling: from energy supply to signaling regulation

Maintenance of bone homeostasis depends on the precise balance between bone formation and bone resorption, a process profoundly regulated by energy metabolism. The glycolytic pathway has emerged as a key determinant of osteoblast and osteoclast fate, functioning beyond energy supply. This review summarizes how multiple signals (e.g., hypoxia-inducible factor-1α/Wnt) promote glycolysis during bone remodeling and highlights that glycolytic enzymes and metabolites (e.g., lactate, lactate dehydrogenase, pyruvate dehydrogenase kinase) act as a "signaling hub" that regulates cell differentiation and function. Cumulative evidence indicates that interfering with specific glycolytic pathways can regulate bone cell differentiation through both energy supply and nonmetabolic signaling mechanisms, providing a novel perspective for understanding bone metabolic diseases. We propose that the glycolytic pathway may function as a signaling hub that integrates metabolic status and regulation of the fate of bone cells. Targeting key nodes of this network represents a promising but preliminary therapeutic direction, and further in vivo and clinical studies are warranted to verify its translational value.