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Hypoxia-driven pathways in bone development, regeneration and disease

Nature Reviews Rheumatology volume 8, pages 358–366 (2012)Cite this article

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Abstract

Adaptation to hypoxia is a critical cellular event both in pathological settings, such as cancer and ischaemia, and in normal development and differentiation. Oxygen is thought to be not only an indispensable metabolic substrate for a variety of in vivo enzymatic reactions, including mitochondrial respiration, but also a key regulatory signal in tissue development and homeostasis by controlling a specific genetic program. Hypoxia-inducible transcription factors (HIFs) HIF-1 and HIF-2 are central mediators of the homeostatic response that enables cells to survive and differentiate in low-oxygen conditions. Genetically altered mice have been used to identify important roles for HIF-1 and HIF-2 as well as vascular endothelial growth factor (VEGF)—a potent angiogenic factor and a downstream target of the HIF pathway—in the regulation of skeletal development, bone homeostasis and haematopoiesis. In this Review, we summarize the current knowledge of HIF signalling in cartilage, bone and blood, and pay particular attention to the complex relationship between HIF and VEGF in these tissues revealed by data from research using animal models. The study of these models expands our understanding of the cell autonomous, paracrine and autocrine effects that mediate the homeostatic responses downstream of HIFs and VEGF.

Key Points

  • Oxygen levels regulate specific signalling cascades, such as the hypoxia-inducible factor (HIF) signalling pathway

  • HIFs are essential mediators of the complex homeostatic responses that enable hypoxic cells to survive and differentiate

  • Vascular endothelial growth factor (VEGF) is a downstream target of the HIF pathway and a potent angiogenic factor

  • HIFs and VEGF have critical roles in skeletal development and bone homeostasis, as well as in haematopoiesis

  • HIFs and VEGF are also crucial for bone regeneration and are involved in osteoarthritis and metastasis of tumours to bone

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Figure 1: The HIF-1α pathway.
Figure 2: The roles of HIF-1α and VEGF in regulating the oxygenation of cartilage during embryonic development.
Figure 3: The HIF and VEGF signalling pathway in bone.
Figure 4: Role of the HIF–VEGF–PlGF pathway in fracture repair.
Figure 5: Role of the HIF pathway in osteoarthritis.
Figure 6: Role of the HIF–VEGF–PIGF pathway in tumour metastasis to bone.

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Acknowledgements

The authors' research is supported by NIH grants RO1 AR04819106 to E. Schipani; FWO G.0569.07, G.0500.08 and G.0982.11 to G. Carmeliet; and Grant 282131 from the European Research Council under the European Union's Seventh Framework Programme (FP7/20072013) to C. Maes.

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  1. Clinical and Experimental Endocrinology, KU Leuven, GHB O&N 1, Herestraat 49 Box 902, 3000, Leuven, Belgium

    Christa Maes & Geert Carmeliet

  2. Departments of Medicine and Anatomy and Cell Biology, Indiana University, 980 W. Walnut Street, Joseph Walther Hall, R3, Rm C110, Indianapolis, 46202, IN, USA

    Ernestina Schipani

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Maes, C., Carmeliet, G. & Schipani, E. Hypoxia-driven pathways in bone development, regeneration and disease. Nat Rev Rheumatol 8, 358–366 (2012). https://doi.org/10.1038/nrrheum.2012.36

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