{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:02:59Z","timestamp":1792803779099,"version":"4.5.0"},"reference-count":52,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:00:00Z","timestamp":1706054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01-AR081318"],"award-info":[{"award-number":["R01-AR081318"]}]},{"name":"Mayo Clinic intramural NIH relief fund","award":["R01-AR081318"],"award-info":[{"award-number":["R01-AR081318"]}],"id":[{"id":"https:\/\/ror.org\/02qp3tb03","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Fibrodysplasia ossificans progressiva (FOP; MIM# 135100) is an ultra-rare congenital disorder caused by gain-of-function point mutations in the Activin receptor A type I (ACVR1, also known as ALK2) gene. FOP is characterized by episodic heterotopic ossification (HO) in skeletal muscles, tendons, ligaments, or other soft tissues that progressively causes irreversible loss of mobility. FOP mutations cause mild ligand-independent constitutive activation as well as ligand-dependent bone morphogenetic protein (BMP) pathway hypersensitivity of mutant ACVR1. BMP signaling is also a key pathway for mediating acquired HO. However, HO is a highly complex biological process involving multiple interacting signaling pathways. Among them, the hypoxia-inducible factor (HIF) and mechanistic target of rapamycin (mTOR) pathways are intimately involved in both genetic and acquired HO formation. HIF-1\u03b1 inhibition or mTOR inhibition reduces HO formation in mouse models of FOP or acquired HO in part by de-amplifying the BMP pathway signaling. Here, we review the recent progress on the mechanisms of the HIF-1\u03b1 and mTOR pathways in the amplification of HO lesions and discuss the future directions and strategies to translate the targeting of HIF-1\u03b1 and the mTOR pathways into clinical interventions for FOP and other forms of HO.<\/jats:p>","DOI":"10.3390\/biom14020147","type":"journal-article","created":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T07:42:16Z","timestamp":1706082136000},"page":"147","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The HIF-1\u03b1 and mTOR Pathways Amplify Heterotopic Ossification"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2340-0739","authenticated-orcid":false,"given":"Haitao","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medicine, Geriatric Medicine & Gerontology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick S.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Medicine, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"The Center for Research in FOP and Related Disorders, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Pignolo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Geriatric Medicine & Gerontology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Medicine, Divisions of Endocrinology, Hospital Internal Medicine, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,24]]},"reference":[{"key":"ref_1","first-page":"219","article-title":"Heterotopic ossification in spinal cord injuries","volume":"66","author":"Goldman","year":"1980","journal-title":"Physiotherapy"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e10172","DOI":"10.1002\/jbm4.10172","article-title":"Heterotopic Ossification: A Comprehensive Review","volume":"3","author":"Meyers","year":"2019","journal-title":"JBMR Plus"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1097\/00003086-197510000-00017","article-title":"Heterotopic ossification","volume":"112","author":"Wharton","year":"1975","journal-title":"Clin. 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