Full Length ArticleGlucose metabolism in bone
Introduction
Bone fractures associated with osteopenia and osteoporosis pose a major health threat especially among the aging population. Despite the recent progress in therapies such as denosumab and abaloparatide, additional safe and effective strategies are necessary to improve bone mass and quality to treat osteoporosis. Because osteoblasts and osteoclasts are the chief cell types regulating bone homeostasis, elucidating the mechanisms that regulate their differentiation and activity is critical not only for understanding bone physiology but also for designing effective bone therapeutics. Extensive studies in the area during the past several decades have mostly focused on the regulation of cell-type-specific marker genes by endocrine or paracrine signals or transcriptional factors [1], [2], [3], [4]. A critical aspect of cell differentiation is the acquisition of specific cellular functions, these including bone matrix deposition by the osteoblast or protease and acid secretion by the osteoclast. However, the bioenergetics in support of the cell-specific physiological activity is just beginning to be explored [5]. This review summarizes the current understanding about the role of glucose metabolism in osteoblasts and osteoclasts.
Section snippets
Glucose metabolism in mammalian cells
Glucose is a major energy source for most mammalian cell types. Upon transport into the cell via the Glut family of transporters down a concentration gradient independent of ATP, glucose is metabolized in the cytoplasm through glycolysis to produce two pyruvate molecules, 2 ATP, and two reducing equivalents in the form of nicotinamide adenine dinucleotide (NADH) [5], [6], [7] (Fig. 1). The first stage of glycolysis culminates in the generation of fructose 1,6-bisphosphate (F1,6 BP), which is
Glucose metabolism in osteoblasts
The bone-forming osteoblasts differentiate through a series of stages characterized by the expression of distinct transcription factors and marker genes [2]. Originated from the mesenchymal progenitors, early osteoblast precursors express the transcription factor Runx2 whereas the more specified preosteoblasts express osterix (Osx or Sp7) (Fig. 2A). Upon further differentiation, the mature osteoblasts activate Atf4 and upregulate the expression of collagen I as well as other matrix proteins
Glucose metabolism in osteoclasts
Osteoclasts are giant, multinucleated cells responsible for resorbing the bone matrix and maintaining mineral homeostasis. Osteoclasts form by differentiation and fusion of monocytic precursors of the macrophage lineage in response to macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL) [1], [4]. During RANKL-induced osteoclast differentiation from murine bone marrow macrophages, both glycolysis and oxidative phosphorylation (OXPHOS) as
Clinical relevance
Systemic dysregulation of glucose metabolism due to the deficiency in either producing (type I) or responding to insulin (type II) is the hallmark of diabetes. Type I Diabetes in particular is associated with a variety of bone complications including reduced bone mineral density, increased fracture risk and poor fracture healing in both humans and rodent models [57], [58]. Historically, the effects of diabetes on the skeleton have been primarily attributed to deleterious effects on osteoblasts
Conclusions
We have highlighted the major findings to date regarding the role and molecular regulation of glucose metabolism in osteoblasts and osteoclasts. A notable knowledge gap exists about the metabolic profile of osteocytes, the predominant cell type in bone. Although one might infer from the historical studies employing bone slices that osteocytes metabolize glucose mainly to lactate, a direct assessment of glucose metabolism in osteocytes is clearly necessary. Nonetheless, the existing literature
Disclosures
All authors state that they have no conflict of interests.
Acknowledgements
Work in Long lab is supported by NIH grants AR060456 and AR055923.
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