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.
Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling / H. Wang, C. Lindborg, V. Lounev, J. Kim, R. McCarrick-Walmsley, M. Xu, L. Mangiavini, J. Groppe, E. Shore, E. Schipani, F. Kaplan, R. Pignolo. - In: JOURNAL OF BONE AND MINERAL RESEARCH. - ISSN 0884-0431. - 31:9(2016 Sep), pp. 1652-1665.
|Titolo:||Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling|
|Parole Chiave:||FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; PRECLINICAL STUDIES; CELL; TISSUE SIGNALING|
|Settore Scientifico Disciplinare:||Settore MED/33 - Malattie Apparato Locomotore|
|Data di pubblicazione:||set-2016|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1002/jbmr.2848|
|Appare nelle tipologie:||01 - Articolo su periodico|
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