Research on the Mechanism of Glycolytic ReprogrammingRegulating Bone Remodeling Imbalance and Osteoporosis
ZHANG Tuanzhuang1, SONG Yuan2, ZHAO Ning1, GAO Yaxiong3*
OP (osteoporosis) is fundamentally characterized by a long-term imbalance between bone formation and bone resorption. In recent years, glycolytic reprogramming in bone-associated cells has been recognized asan important metabolic link connecting aging, estrogen deficiency, diabetes, hypoxia, and chronic inflammation withabnormal bone remodeling. Glycolysis influences the fate and function of osteoblasts, osteoclasts, and bone immunecells by regulating glucose uptake and glycolytic flux, ATP (adenosine triphosphate) and biosynthetic substrate supply, redox homeostasis, lactate production/transport, and lactylation. In the osteogenic lineage, moderate enhancementof glycolysis facilitates osteogenic differentiation, matrix synthesis, and mineralization, whereas impaired glycolyticadaptation may result in insufficient bone formation. In contrast, RANKL (receptor activator of nuclear factor-κBligand)/NF-κB (nuclear factor-κB)/HIF-1α (hypoxia-inducible factor-1α)-driven enhancement of glycolysis in osteoclasts promotes bone resorption by supporting cell fusion, cytoskeletal remodeling, and acidification of resorptionlacunae through metabolic nodes such as PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3), PKM2(pyruvate kinase M2), and LDHA (lactate dehydrogenase A)/MCT (monocarboxylate transporter). AMPK (adenosinemonophosphate-activated protein kinase) senses cellular energy status and modulates mTOR (mechanistic target ofrapamycin) signaling to coordinate glycolytic energy supply with anabolic demands, thereby serving as a key metabolic checkpoint that determines how effectively glycolysis supports osteogenic differentiation and bone formation.Lactate/lactylation exhibits a pronounced “double-edged sword” effect: in transient and moderate microenvironmentsdominated by tissue repair and osteogenic coupling, lactate can promote osteogenic differentiation and bone formation through pathways involving p300 (histone acetyltransferase p300)/H3K18la (histone H3 lysine 18 lactylation);however, in persistent, high-lactate-burden microenvironments dominated by chronic inflammation and osteoclastactivity, lactate accumulation may act in concert with acidification, MCT-mediated transport, and immunometabolicremodeling to aggravate bone loss. This review summarizes the key metabolic nodes, cell-specific effects, and potential intervention strategies involved in glycolytic reprogramming-mediated dysregulation of bone remodeling,with the aim of providing new theoretical insights and research directions for metabolism-targeted therapy of OP.
CN
EN