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The role of osteoblasts in energy homeostasis

Abstract

Osteoblasts are specialized mesenchymal cells that synthesize bone matrix and coordinate the mineralization of the skeleton. These cells work in harmony with osteoclasts, which resorb bone, in a continuous cycle that occurs throughout life. The unique function of osteoblasts requires substantial amounts of energy production, particularly during states of new bone formation and remodelling. Over the last 15 years, studies have shown that osteoblasts secrete endocrine factors that integrate the metabolic requirements of bone formation with global energy balance through the regulation of insulin production, feeding behaviour and adipose tissue metabolism. In this article, we summarize the current understanding of three osteoblast-derived metabolic hormones (osteocalcin, lipocalin and sclerostin) and the clinical evidence that suggests the relevance of these pathways in humans, while also discussing the necessity of specific energy substrates (glucose, fatty acids and amino acids) to fuel bone formation and promote osteoblast differentiation.

Key points

  • Osteoblasts are bone-forming cells that respond to metabolic hormones and produce at least three endocrine factors that influence whole-body metabolism.

  • Osteocalcin acts via a feedforward endocrine loop to regulate pancreatic insulin production and insulin sensitivity.

  • Osteoblast-derived lipocalin regulates feeding behaviour.

  • Sclerostin exerts control over bone tissue acquisition while also regulating WNT signalling and fatty acid synthesis in adipose tissue depots.

  • The utilization of glucose, fatty acids and amino acids by the osteoblast is associated with the stage of differentiation and the energetic demands for matrix production.

  • Key osteoblast developmental signals, including WNT–β-catenin, Notch and HIF, coordinate osteoblastic activity and intermediary metabolism.

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Fig. 1: Endocrine effects of osteocalcin, lipocalin and sclerostin.
Fig. 2: Overview of pathways involved in osteogenic glucose metabolism.
Fig. 3: Overview of pathways involved in osteogenic fatty acid metabolism.
Fig. 4: Overview of pathways involved in glutamine metabolism.

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Acknowledgements

The authors gratefully acknowledge the work by other investigators that has not been cited in this manuscript because of space limitations. Work in the authors’ laboratories is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK099134, R.C.R) and the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development (BX003724, R.C.R; BX001234, T.L.C.). T.L.C is also the recipient of a Senior Research Career Scientist Award from the Department of Veterans Affairs.

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Glossary

Bone modelling

The deposition or resorption of bone matrix on separate bone surfaces to retain overall bone shape.

Bone remodelling

The consecutive resorption and then deposition of bone matrix at the same skeletal site, which is often used to replace old or damaged tissue.

Tricarboxylic acid (TCA) cycle

The series of chemical reactions in the mitochondria that liberates energy from nutrient substrates.

WNT–β-catenin signalling

A conserved signalling pathway requiring a WNT ligand, Frizzled receptor and low-density lipoprotein receptor-related protein 5 (LRP5)–LRP6 co-receptor that regulates the stability of the transcription factor β-catenin.

Calvarial cells

A population of cells isolated from the calvarial bones of neonatal rodents, which is enriched in osteoblastic cells.

Warburg metabolism

The metabolism of glucose by glycolysis rather than oxidative phosphorylation even under aerobic conditions.

Histone acetylation

The modification of lysine residues in the N-terminal tail of histones with an acetyl group to increase gene expression.

Chylomicron

Lipoprotein particles produced in the gut consisting of protein, phospholipids, triglycerides and cholesterol.

Coffin–Lowry syndrome

A rare genetic disorder characterized by skeletal deformities, short stature and delayed intellectual development linked to mutations in the RPS6KA3 gene.

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Dirckx, N., Moorer, M.C., Clemens, T.L. et al. The role of osteoblasts in energy homeostasis. Nat Rev Endocrinol 15, 651–665 (2019). https://doi.org/10.1038/s41574-019-0246-y

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