title: Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling.
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 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.
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.|The Center for Research in FOP and Related Disorders, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.|The Center for Research in FOP and Related Disorders, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Carter
authors.initials: C
authors.lastname: Lindborg
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.|The Center for Research in FOP and Related Disorders, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Vitali
authors.initials: V
authors.lastname: Lounev
authors.affiliation: Department of Medicine, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.|The Center for Research in FOP and Related Disorders, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: McCarrick-Walmsley
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.|The Center for Research in FOP and Related Disorders, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Meiqi
authors.initials: M
authors.lastname: Xu
authors.affiliation: Departments of Medicine and Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Mangiavini
authors.affiliation: Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas, TX, USA.
authors.forename: Jay C
authors.initials: JC
authors.lastname: Groppe
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.|The Center for Research in FOP and Related Disorders, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.|Department of Genetics, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
authors.affiliation: Departments of Medicine and Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Ernestina
authors.initials: E
authors.lastname: Schipani
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.|The Center for Research in FOP and Related Disorders, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.|Department of Medicine, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Kaplan
authors.affiliation: Department of Orthopaedic Surgery, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.|The Center for Research in FOP and Related Disorders, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.|Department of Medicine, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Pignolo
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D020219:Chondrogenesis; D004195:Disease Models, Animal; D011992:Endosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D008024:Ligands; D008297:Male; D008822:Mice, Transgenic; D008954:Models, Biological; D009221:Myositis Ossificans / Q000473:pathology; D009999:Ossification, Heterotopic / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D014080:Tooth Exfoliation / Q000473:pathology; D014094:Tooth, Deciduous / Q000473:pathology
chemical_list: D019485:Bone Morphogenetic Proteins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D030201:Activin Receptors, Type I
keywords: CELL/TISSUE SIGNALING; FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; PRECLINICAL STUDIES