Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling
dc.contributor.author | Wang, Haitao | |
dc.contributor.author | Lindborg, Carter | |
dc.contributor.author | Lounev, Vitali | |
dc.contributor.author | Kim, Jung‐hoon | |
dc.contributor.author | Mccarrick‐walmsley, Ruth | |
dc.contributor.author | Xu, Meiqi | |
dc.contributor.author | Mangiavini, Laura | |
dc.contributor.author | Groppe, Jay C | |
dc.contributor.author | Shore, Eileen M | |
dc.contributor.author | Schipani, Ernestina | |
dc.contributor.author | Kaplan, Frederick S | |
dc.contributor.author | Pignolo, Robert J | |
dc.date.accessioned | 2016-10-17T21:20:11Z | |
dc.date.available | 2017-11-01T15:31:29Z | en |
dc.date.issued | 2016-09 | |
dc.identifier.citation | Wang, Haitao; Lindborg, Carter; Lounev, Vitali; Kim, Jung‐hoon ; Mccarrick‐walmsley, Ruth ; Xu, Meiqi; Mangiavini, Laura; Groppe, Jay C; Shore, Eileen M; Schipani, Ernestina; Kaplan, Frederick S; Pignolo, Robert J (2016). "Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling." Journal of Bone and Mineral Research 31(9): 1652-1665. | |
dc.identifier.issn | 0884-0431 | |
dc.identifier.issn | 1523-4681 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/134262 | |
dc.description.abstract | Hypoxia and inflammation are implicated in the episodic induction of heterotopic endochondral ossification (HEO); however, the molecular mechanisms are unknown. HIFâ 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 HIFâ 1α in fibrodysplasia ossificans progressiva (FOP), the most catastrophic form of HEO in humans. We found that HIFâ 1α increases the intensity and duration of canonical bone morphogenetic protein (BMP) signaling through Rabaptin 5 (RABEP1)â 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 HIFâ 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 oxygenâ 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 HIFâ 1α in the hypoxic amplification of BMP signaling and in the episodic induction of HEO in FOP and further identifies HIFâ 1α as a therapeutic target for FOP and perhaps nongenetic forms of HEO. © 2016 American Society for Bone and Mineral Research. | |
dc.publisher | Wiley Periodicals, Inc. | |
dc.subject.other | FIBRODYSPLASIA OSSIFICANS PROGRESSIVA | |
dc.subject.other | CELL/TISSUE SIGNALING | |
dc.subject.other | PRECLINICAL STUDIES | |
dc.title | Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling | |
dc.type | Article | en_US |
dc.rights.robots | IndexNoFollow | |
dc.subject.hlbsecondlevel | Internal Medicine and Specialities | |
dc.subject.hlbtoplevel | Health Sciences | |
dc.description.peerreviewed | Peer Reviewed | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/134262/1/jbmr2848_am.pdf | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/134262/2/jbmr2848.pdf | |
dc.identifier.doi | 10.1002/jbmr.2848 | |
dc.identifier.source | Journal of Bone and Mineral Research | |
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dc.owningcollname | Interdisciplinary and Peer-Reviewed |
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