{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:12:23Z","timestamp":1772118743009,"version":"3.50.1"},"reference-count":68,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T00:00:00Z","timestamp":1706313600000},"content-version":"vor","delay-in-days":1152,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2022,7,3]],"date-time":"2022-07-03T00:00:00Z","timestamp":1656806400000},"content-version":"vor","delay-in-days":579,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR072052"],"award-info":[{"award-number":["R01AR072052"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R21AR074584"],"award-info":[{"award-number":["R21AR074584"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR072052"],"award-info":[{"award-number":["R01AR072052"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R21AR074584"],"award-info":[{"award-number":["R21AR074584"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>\u2003<\/jats:title>\n                    <jats:p>Fibrodysplasia ossificans progressiva (FOP) is a devastating disease of progressive heterotopic bone formation for which effective treatments are currently unavailable. FOP is caused by dominant gain-of-function mutations in the receptor ACVR1 (also known as ALK2), which render the receptor inappropriately responsive to activin ligands. In previous studies, we developed a genetic mouse model of FOP that recapitulates most clinical aspects of the disease. In this model, genetic loss of the wild-type Acvr1 allele profoundly exacerbated heterotopic ossification, suggesting the hypothesis that the stoichiometry of wild-type and mutant receptors dictates disease severity. Here, we tested this model by producing FOP mice that conditionally overexpress human wild-type ACVR1. Injury-induced heterotopic ossification (HO) was completely blocked in FOP mice when expression of both the mutant and wild-type receptor were targeted to Tie2-positive cells, which includes fibro\/adipogenic progenitors (FAPs). Perinatal lethality of Acvr1R206H\/+ mice was rescued by constitutive ACVR1 overexpression, and these mice survived to adulthood at predicted Mendelian frequencies. Constitutive overexpression of ACVR1 also provided protection from spontaneous abnormal skeletogenesis, and the incidence and severity of injury-induced HO in these mice was dramatically reduced. Analysis of pSMAD1\/5\/8 signaling both in cultured cells and in vivo indicates that ACVR1 overexpression functions cell-autonomously by reducing osteogenic signaling in response to activin A. We propose that ACVR1 overexpression inhibits HO by decreasing the abundance of ACVR1(R206H)-containing signaling complexes at the cell surface while increasing the representation of activin-A-bound non-signaling complexes comprised of wild-type ACVR1. \u00a9 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jbmr.4617","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T01:45:07Z","timestamp":1653961507000},"page":"2077-2093","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Overexpression of Wild-Type ACVR1 in Fibrodysplasia Ossificans Progressiva Mice Rescues Perinatal Lethality and Inhibits Heterotopic Ossification"],"prefix":"10.1093","volume":"37","author":[{"given":"Masakazu","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Department of Molecular and Cell Biology University of Connecticut Stem Cell Institute, University of Connecticut Storrs CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean J","family":"Stoessel","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology University of Connecticut Stem Cell Institute, University of Connecticut Storrs CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoko","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology University of Connecticut Stem Cell Institute, University of Connecticut Storrs CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4605-8921","authenticated-orcid":false,"given":"David J","family":"Goldhamer","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology University of Connecticut Stem Cell Institute, University of Connecticut Storrs CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,5,30]]},"reference":[{"issue":"3","key":"2024012714062005500_jbmr4617-bib-0001","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1080\/16501970510027628","article-title":"Heterotopic ossification: a review","volume":"37","author":"Bossche","year":"2005","journal-title":"J Rehabil Med."},{"issue":"2","key":"2024012714062005500_jbmr4617-bib-0002","doi-asserted-by":"crossref","first-page":"116","DOI":"10.5435\/00124635-200403000-00007","article-title":"Heterotopic ossification","volume":"12","author":"Kaplan","year":"2004","journal-title":"J Am Acad Orthop Surg."},{"issue":"10","key":"2024012714062005500_jbmr4617-bib-0003","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1007\/s00296-015-3301-6","article-title":"Osteochondromas in fibrodysplasia ossificans progressiva: a widespread trait with a streaking but overlooked appearance when arising at femoral bone end","volume":"35","author":"Morales-Piga","year":"2015","journal-title":"Rheumatol Int."},{"issue":"5","key":"2024012714062005500_jbmr4617-bib-0004","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/ng1783","article-title":"A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva","volume":"38","author":"Shore","year":"2006","journal-title":"Nat Genet."},{"issue":"11","key":"2024012714062005500_jbmr4617-bib-0005","doi-asserted-by":"crossref","first-page":"7149","DOI":"10.1074\/jbc.M801681200","article-title":"Constitutively activated ALK2 and increased SMAD1\/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva","volume":"284","author":"Fukuda","year":"2009","journal-title":"J Biol Chem."},{"issue":"5","key":"2024012714062005500_jbmr4617-bib-0006","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1002\/stem.1633","article-title":"Alk2 regulates 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