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Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling
Author(s) -
Wang Haitao,
Lindborg Carter,
Lounev Vitali,
Kim JungHoon,
McCarrickWalmsley Ruth,
Xu Meiqi,
Mangiavini Laura,
Groppe Jay C,
Shore Eileen M,
Schipani Ernestina,
Kaplan Frederick S,
Pignolo Robert J
Publication year - 2016
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.2848
Subject(s) - fibrodysplasia ossificans progressiva , endochondral ossification , bmpr2 , bone morphogenetic protein , heterotopic ossification , hypoxia (environmental) , microbiology and biotechnology , signal transduction , biology , inflammation , cancer research , immunology , chemistry , anatomy , genetics , cartilage , organic chemistry , oxygen , gene
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 Acvr1 Q207D/+ 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. © 2016 American Society for Bone and Mineral Research.