Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling

Haitao Wang, Carter Lindborg, Vitali Lounev, Jung Hoon Kim, Ruth McCarrick-Walmsley, Meiqi Xu, Laura Mangiavini, Jay C. Groppe, Eileen M. Shore, Ernestina Schipani, Frederick S. Kaplan, Robert J. Pignolo

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Hypoxia and inflammation are implicated in the episodic induction of heterotopic endochondral ossification (HEO); however, the molecular mechanisms are unknown. HIF-1α integrates the cellular response to both hypoxia and inflammation and is a prime candidate for regulating HEO. We investigated the role of hypoxia and HIF-1α in fibrodysplasia ossificans progressiva (FOP), the most catastrophic form of HEO in humans. We found that HIF-1α increases the intensity and duration of canonical bone morphogenetic protein (BMP) signaling through Rabaptin 5 (RABEP1)-mediated retention of Activin A receptor, type I (ACVR1), a BMP receptor, in the endosomal compartment of hypoxic connective tissue progenitor cells from patients with FOP. We further show that early inflammatory FOP lesions in humans and in a mouse model are markedly hypoxic, and inhibition of HIF-1α by genetic or pharmacologic means restores canonical BMP signaling to normoxic levels in human FOP cells and profoundly reduces HEO in a constitutively active Acvr1Q207D/+ mouse model of FOP. Thus, an inflammation and cellular oxygen-sensing mechanism that modulates intracellular retention of a mutant BMP receptor determines, in part, its pathologic activity in FOP. Our study provides critical insight into a previously unrecognized role of HIF-1α in the hypoxic amplification of BMP signaling and in the episodic induction of HEO in FOP and further identifies HIF-1α as a therapeutic target for FOP and perhaps nongenetic forms of HEO.

Original languageEnglish (US)
Pages (from-to)1652-1665
Number of pages14
JournalJournal of Bone and Mineral Research
Volume31
Issue number9
DOIs
StatePublished - Sep 1 2016

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Keywords

  • CELL/TISSUE SIGNALING
  • FIBRODYSPLASIA OSSIFICANS PROGRESSIVA
  • PRECLINICAL STUDIES

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Wang, H., Lindborg, C., Lounev, V., Kim, J. H., McCarrick-Walmsley, R., Xu, M., Mangiavini, L., Groppe, J. C., Shore, E. M., Schipani, E., Kaplan, F. S., & Pignolo, R. J. (2016). Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling. Journal of Bone and Mineral Research, 31(9), 1652-1665. https://doi.org/10.1002/jbmr.2848