Glucose metabolism in bone

Abstract

The adult human skeleton is a multifunctional organ undergoing constant remodeling through the opposing activities of the bone-resorbing osteoclast and the bone-forming osteoblast. The exquisite balance between bone resorption and bone formation is responsible for bone homeostasis in healthy adults. However, evidence has emerged that such a balance is likely disrupted in diabetes where systemic glucose metabolism is dysregulated, resulting in increased bone frailty and osteoporotic fractures. These findings therefore underscore the significance of understanding the role and regulation of glucose metabolism in bone under both normal and pathological conditions. Recent studies have shed new light on the metabolic plasticity and the critical functions of glucose metabolism during osteoclast and osteoblast differentiation. Moreover, these studies have begun to identify intersections between glucose metabolism and the growth factors and transcription factors previously known to regulate osteoblasts and osteoclasts. Here we summarize the current knowledge in the nascent field, and suggest that a fundamental understanding of glucose metabolic pathways in the critical bone cell types may open new avenues for developing novel bone therapeutics.

Keywords: Bone; Diabetes; Glucose; Glycolysis; Metabolism; Mitochondria; Osteoblast; Osteoclast; Osteoporosis; Oxidative phosphorylation (OXPHOS).

Fig. 1

Glucose metabolism in mammalian cells. Protein abbreviations: GLUT – Glucose Transporter; HK – Hexokinase; PGI – Phosphoglucose Isomerase. PFK – Phosphofructokinase; TPI –Triose Phosphate Isomerase; GAPDH – Glyceraldehyde 3-phosphate Dehydrogenase; PGK – Phosphoglycerate Kinase; PGAM –Phosphoglycerate Mutase; ENO – Enolase; PKM – Pyruvate Kinase, Muscle; LDH – Lactate Dehydrogenase; PDH – Pyruvate Dehydrogenase; ACLY: ATP citrate lyase; MCT – Monocarboxylate Transporter. Metabolite abbreviations: G6P – Glucose 6-phosphate; F6P – Fructose 6-phosphate; F1,6BP – Fructose 1,6-bisphosphate; DHAP – Dihydroxyacetone Phosphate; G3P – Glyceraldehyde 3-phosphate; 1,3BPG – 1,3-Bisphosphoglycerate; 3PG – 3-Phosphoglycerate; 2PG – 2-Phosphoglycerate; PEP – Phosphoenolpyruvate.

Fig. 2

Regulation of glucose metabolism in osteoblast lineage. (A) A schematic of osteoblast differentiation. Representative marker genes are denoted at specific stages. (B) Signal pathways regulating glucose metabolism during osteoblast differentiation. PTH – Parathyroid Hormone. PTH1R – Parathyroid Hormone 1 Receptor. IGF1 – Insulin Like Growth Factor 1. IGF1R –Insulin Like Growth Factor 1 Receptor. FZD – Frizzled. LRP5/6 – Low Density Lipoprotein Receptor-Related Protein 5 or 6. cAMP: Cyclic Adenosine Monophosphate. Hif1a - Hypoxia Inducible Factor 1a. GLUT1 – Glucose Transporter 1; HK2 – Hexokinase 2; LDHA – Lactate Dehydrogenase A; PDK1 – Pyruvate Dehydrogenase Kinase 1. Bent arrows denote gene transcription. Arrows and blocked arrows indicate stimulation and inhibition, respectively.

Fig. 3

Metabolic regulation during osteoclast differentiation. Both glycolysis and OXPHOS increase during osteoclastogenesis. MCSF: macrophage colony stimulating factor; RANKL: receptor activator of nuclear factor kappa-B ligand.