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Metabolic regulation of skeletal cell fate and function

Nature Reviews Endocrinology (2024)Cite this article

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Abstract

Bone development and bone remodelling during adult life are highly anabolic processes requiring an adequate supply of oxygen and nutrients. Bone-forming osteoblasts and bone-resorbing osteoclasts interact closely to preserve bone mass and architecture and are often located close to blood vessels. Chondrocytes within the developing growth plate ensure that bone lengthening occurs before puberty, but these cells function in an avascular environment. With ageing, numerous bone marrow adipocytes appear, often with negative effects on bone properties. Many studies have now indicated that skeletal cells have specific metabolic profiles that correspond to the nutritional microenvironment and their stage-specific functions. These metabolic networks provide not only skeletal cells with sufficient energy, but also biosynthetic intermediates that are necessary for proliferation and extracellular matrix synthesis. Moreover, these metabolic pathways control redox homeostasis to avoid oxidative stress and safeguard cell survival. Finally, several intracellular metabolites regulate the activity of epigenetic enzymes and thus control the fate and function of skeletal cells. The metabolic profile of skeletal cells therefore not only reflects their cellular state, but can also drive cellular activity. Insight into skeletal cell metabolism will thus not only advance our understanding of skeletal development and homeostasis, but also of skeletal disorders, such as osteoarthritis, diabetic bone disease and bone malignancies.

Key points

  • Skeletal stem and progenitor cells display a high metabolic flexibility, and are likely to adapt to changing microenvironments.

  • Osteoblasts use glycolysis and fatty acid oxidation as major energy sources, whereas they use glutamine metabolism for biosynthesis and prevention of oxidative stress.

  • Bone marrow adipocytes release fatty acids upon systemic energy deficit to support osteoblast function.

  • Chondrocytes are well-adapted to their hypoxic and fatty acid-scarce microenvironment, as they rely on glycolysis for bioenergetics and glutamine metabolism for biosynthesis, redox balance and epigenetic regulation.

  • Osteoclast differentiation depends on oxidative phosphorylation, primarily supplied by glucose and fatty acid oxidation.

  • Metabolic disturbance is linked to skeletal cell dysfunction during bone pathology, and bone-metastatic and leukaemic cells hijack skeletal cell metabolism to support their tumorigenic spread.

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Fig. 1: Differentiation of bone-resident cell types.
Fig. 2: Metabolic features of skeletal cells.
Fig. 3: Metabolic profile of skeletal stem and progenitor cells, and their osteogenic and adipogenic descendants.
Fig. 4: Metabolic regulation of chondrocyte function.
Fig. 5: Metabolic regulation of osteoclast differentiation and activity.

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Acknowledgements

The authors thank Fonds voor Wetenschappelijk Onderzoek-Flanders for funding: EOS-G0F8218N, G0B3418N, G0C5120, G071321N, Hercules-I013518N.

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  1. Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium

    Steve Stegen & Geert Carmeliet

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Stegen, S., Carmeliet, G. Metabolic regulation of skeletal cell fate and function. Nat Rev Endocrinol (2024). https://doi.org/10.1038/s41574-024-00969-x

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