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Abstract

The hypoxia inducible factors (Hifs) are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary for osteoblast specification, but in mature bone, loss of Hif-1 in osteoblasts resulted in a more rapid accumulation of bone. These findings suggested that Hif-1 exerts distinct developmental functions and acts as a negative regulator of bone formation. To investigate the function of Hif-1α in osteoanabolic signaling, we assessed the effect of Hif-1α loss-of-function on bone formation in response to intermittent parathyroid hormone (PTH). Mice lacking Hif-1α in osteoblasts and osteocytes form more bone in response to PTH, likely through a larger increase in osteoblast activity and increased sensitivity to the hormone. Consistent with this effect, exposure of primary mouse osteoblasts to PTH resulted in the rapid induction of Hif-1α protein levels via a post-transcriptional mechanism. The enhanced anabolic response appears to result from the removal of Hif-1α-mediated suppression of β-catenin transcriptional activity. Together, these data indicate that Hif-1α functions in the mature skeleton to restrict osteoanabolic signaling. The availability of pharmacological agents that reduce Hif-1α function suggests the value in further exploration of this pathway to optimize the therapeutic benefits of PTH.

Document Type

Article

Publication Date

5-13-2014

Notes/Citation Information

Published in Bone Research, v. 2, article 14005, p. 1-10.

© 2014 Sichuan University. All rights reserved

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

Digital Object Identifier (DOI)

http://dx.doi.org/10.1038/boneres.2014.5

Funding Information

Support was provided by a Career Development Award (RCR, BX001284) from the Veterans Administration.

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