Sugar Metabolism Emerges as a Master Switch Controlling Bone Rebuilding

Bone is not the inert scaffold that most people imagine. It is a living tissue that is demolished and rebuilt continuously throughout life, a process known as bone remodeling, in which specialized cells called osteoclasts break down old bone while osteoblasts lay down fresh matrix. Keeping these two opposing forces in balance is essential for skeletal strength, and when the balance tips, diseases such as osteoporosis, inflammatory bone loss and osteoarthritis follow. A new review published in Molecular Biology Reports argues that the answer to how this balance is orchestrated may lie in one of the oldest and most fundamental biochemical pathways in biology: glycolysis, the stepwise breakdown of glucose that cells have used to generate energy for billions of years.

The review, authored by Haoyi Song, Shao Cheng, Shang Ma and colleagues at Henan University of Chinese Medicine, synthesizes decades of evidence showing that glycolysis does far more than simply fuel bone cells. Instead, the authors propose that the glycolytic pathway operates as a genuine signaling hub, a network of enzymes and metabolites that directly instructs bone cells on how to differentiate, mature and function. This reframing matters because it suggests that the metabolic state of a bone cell is not merely a consequence of its identity but an active determinant of it, opening the door to therapies that could treat metabolic bone disease by manipulating sugar metabolism itself.

The technical story begins with glucose uptake. Bone cells express glucose transporter type 1, or Glut1, on their surface, and radiotracer studies in living mice have shown that bone takes up a striking amount of circulating glucose. Once inside, glucose is funneled through the glycolytic cascade, culminating in the conversion of pyruvate to lactate by lactate dehydrogenase, even in the presence of abundant oxygen. This phenomenon, often called aerobic glycolysis or the Warburg effect, seems wasteful at first glance because it extracts far less ATP per glucose molecule than oxidative phosphorylation would. Yet osteoblasts rely heavily on it, and genetic experiments have demonstrated that blocking glucose uptake or glycolytic flux in osteoblast precursors severely impairs bone formation.

Why would a cell that needs to build mineralized tissue choose such an inefficient energy strategy? Part of the answer lies in the biosynthetic demands of differentiation. As osteoblasts mature, they must mass-produce collagen, alkaline phosphatase and other matrix proteins, and glycolytic intermediates feed directly into the pathways that generate the building blocks for these molecules. Work on the transcription factor Runx2 has shown that glucose uptake and this master regulator of osteoblast identity synergize: glucose metabolism itself helps activate the genetic program of bone formation. Wnt signaling, a central pathway in skeletal biology, induces the Warburg effect through activation of the mTORC2 complex, and increased glycolysis has been shown to mediate the bone-forming effects of Wnt7b. In other words, the signals that tell a cell to become an osteoblast simultaneously rewire its metabolism, and that metabolic rewiring feeds back to reinforce the differentiation program.

Hypoxia adds another layer of control. The bone marrow is a surprisingly oxygen-poor environment, with direct measurements in live animals revealing very low local oxygen concentrations. Under these conditions, the hypoxia-inducible factor HIF-1α accumulates and drives the expression of glycolytic enzymes, boosting glucose consumption. In osteoblasts, HIF1α-driven glycolysis is required for normal bone formation, and activating the pathway can partially alleviate the skeletal symptoms of type 1 diabetes in experimental models. In osteoclasts, the relationship is more nuanced: HIF-1α does not appear to be essential for the differentiation of these bone-resorbing cells, but it enhances their resorptive activity, and hypoxia has been shown to increase both acid secretion and bone degradation in settings such as mandibular osteotomy.

Osteoclasts, the demolition crew of the skeleton, undergo their own dramatic metabolic shifts. Early studies dating back to the 1960s established that bone tissue metabolizes glucose aerobically, and modern work has shown that osteoclast precursors display dynamic increases in glucose metabolism at the earliest stages of differentiation induced by RANKL, the key cytokine driving osteoclastogenesis. Both aerobic glycolysis and mitochondrial respiration are required for full osteoclast differentiation, and the glycolytic enzyme lactate dehydrogenase has been shown to potentiate osteoclast formation through activation of NFATc1, the pivotal transcription factor that orchestrates the osteoclast genetic program. Pyruvate dehydrogenase kinases, which throttle the flow of pyruvate into the mitochondrial Krebs cycle, also shape osteoclast behavior; deficiency of PDK2 protects mice from ovariectomy-induced bone loss by regulating the RANKL-NFATc1 axis during osteoclast differentiation.

Perhaps the most striking findings concern glycolytic enzymes acting outside their classical metabolic roles. Pyruvate kinase M2, the embryonic isoform of the final glycolytic enzyme, can be phosphorylated by the cell adhesion molecule IgSF11, and this modification regulates osteoclast differentiation and prevents pathological bone loss in models. Phosphoglycerate kinase 1, another glycolytic enzyme, protects osteoblasts from the damaging effects of glucocorticoids such as dexamethasone by activating the NRF2 antioxidant signaling cascade when it is depleted. Aldolase, the enzyme that splits fructose-1,6-bisphosphate, physically interacts with the vacuolar H+-ATPase that osteoclasts use to acidify the resorption lacuna, directly linking sugar metabolism to the machinery of bone degradation. Even fructose-1,6-bisphosphate itself, a mid-pathway metabolite, inhibits osteoclastogenesis by attenuating RANKL-induced NF-κB and NFATc1 signaling.

Lactate, long dismissed as a metabolic waste product, has emerged as a signaling molecule in its own right. Osteoblasts express the lactate receptor GPR81 and the transporter MCT1, and lactate has been shown to induce osteoblast differentiation by stabilizing HIF1α, to enhance the bone-anabolic effect of parathyroid hormone through GPR81-PKC-Akt signaling, and to mediate the bone-building effects of high-intensity interval training. Exercise studies have demonstrated that lactate signaling through Gpr81 increases bone mass, and endothelial cell-derived lactate can trigger histone lactylation in bone marrow mesenchymal stem cells, a recently discovered epigenetic modification in which lactate-derived lactyl groups are attached to histone proteins, altering gene expression. Histone H3K18 lactylation in particular marks active enhancers, and a positive feedback loop between H3K18 lactylation and hexokinase 2 has been shown to promote bone formation in pathological settings, while exercise-induced H3K18 lactylation inhibits osteoclast activity and protects against osteoporosis.

The review also connects glycolysis to RNA modification and chromatin regulation. N6-methyladenosine, the most abundant internal chemical mark on messenger RNA, is influenced by one-carbon metabolism and glycolytic flux, and the methyltransferase METTL3 has been shown to regulate glycolysis during dental pulp stem cell differentiation and, via histone lactylation, to promote ossification by enhancing m6A methylation of BMP2 messenger RNA. Protein arginine methyltransferases add yet another dimension: PRMT6 epigenetically drives a metabolic switch from fatty acid oxidation toward glycolysis and promotes osteoclast differentiation during osteoporosis, while CARM1-mediated arginine methylation of a phosphatase regulator affects both osteogenic and osteoclastic differentiation through glucose metabolism.

The therapeutic implications are tantalizing but, as the authors are careful to emphasize, preliminary. Interfering with specific glycolytic nodes can regulate bone cell differentiation through both energy-supply and nonmetabolic signaling mechanisms, and early preclinical work is already exploring this space: bone-targeting, ROS-responsive nanoplatforms designed for precision glycolysis inhibition in postmenopausal osteoporosis, PRMT6 inhibitors that promote fracture healing by modulating osteoclast glucose metabolism, and natural compounds such as isoliquiritigenin that restore bone homeostasis by enhancing the ERK-mTOR-HIF-1α-glycolytic axis in bone marrow stromal cells. The challenge ahead is selectivity, because glycolysis is essential to virtually every cell in the body, and systemically blocking it would be catastrophic. The authors propose that targeting key nodes of the glycolytic signaling network represents a promising direction, but they stress that further in vivo and clinical studies are warranted to verify its translational value. If those studies succeed, the humble pathway that textbooks describe as simple sugar burning may become one of the most unexpected targets in the fight against osteoporosis and other diseases of the skeleton.

Subject of Research: The role of glycolysis as an energy source and signaling hub regulating osteoblast and osteoclast differentiation during bone remodeling

Article Title: Glycolysis in bone remodeling: from energy supply to signaling regulation

Article References: Song, H., Cheng, S., Ma, S., Wang, Z., Liu, B., Dan, Y., Li, J., Wei, B., Yuan, R., Wu, S., Shen, J., & Wang, S. (2026). Glycolysis in bone remodeling: from energy supply to signaling regulation. Molecular Biology Reports, 53(1), Article 1645. https://doi.org/10.1007/s11033-026-12832-5

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12832-5

Keywords: glycolysis, bone remodeling, osteoblasts, osteoclasts, lactate, HIF-1α, histone lactylation, metabolic reprogramming, osteoporosis, NFATc1, Wnt signaling, epigenetic regulation