{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T14:23:12Z","timestamp":1793283792262,"version":"4.5.0"},"reference-count":96,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2017,10,7]],"date-time":"2017-10-07T00:00:00Z","timestamp":1507334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100013117","name":"International Fibrodysplasia Ossificans Progressiva Association","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013117","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,2,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Heterotopic ossification (HO) is a clinical condition that often reduces mobility and diminishes quality of life for affected individuals. The most severe form of progressive HO occurs in those with fibrodysplasia ossificans progressiva (FOP; OMIM #135100), a genetic disorder caused by a recurrent heterozygous gain-of-function mutation (R206H) in the bone morphogenetic protein (BMP) type I receptor ACVR1\/ALK2. In individuals with FOP, episodes of HO frequently follow injury. The first sign of active disease is commonly an inflammatory \u201cflare-up\u201d that precedes connective tissue degradation, progenitor cell recruitment, and endochondral HO. We used a conditional-on global knock-in mouse model expressing Acvr1R206H (referred to as Acvr1cR206H\/+) to investigate the cellular and molecular inflammatory response in FOP lesions following injury. We found that the Acvr1 R206H mutation caused increased BMP signaling in posttraumatic FOP lesions and early divergence from the normal skeletal muscle repair program with elevated and prolonged immune cell infiltration. The proinflammatory cytokine response of TNF\u03b1, IL-1\u03b2, and IL-6 was elevated and prolonged in Acvr1cR206H\/+ lesions and in Acvr1cR206H\/+ mast cells. Importantly, depletion of mast cells and macrophages significantly impaired injury-induced HO in Acvr1cR206H\/+ mice, reducing injury-induced HO volume by \u223c50% with depletion of each cell population independently, and \u223c75% with combined depletion of both cell populations. Together, our data show that the immune system contributes to the initiation and development of HO in FOP. Further, the expression of Acvr1R206H in immune cells alters cytokine expression and cellular response to injury and unveils novel therapeutic targets for treatment of FOP and nongenetic forms of HO. \u00a9 2017 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.3304","type":"journal-article","created":{"date-parts":[[2017,10,7]],"date-time":"2017-10-07T12:36:57Z","timestamp":1507379817000},"page":"269-282","source":"Crossref","is-referenced-by-count":155,"title":["Depletion of Mast Cells and Macrophages Impairs Heterotopic Ossification in an <i>Acvr1R206H<\/i> Mouse Model of Fibrodysplasia Ossificans Progressiva"],"prefix":"10.1093","volume":"33","author":[{"given":"Michael R","family":"Convente","sequence":"first","affiliation":[{"name":"The Center for Research in FOP and Related DisordersPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"},{"name":"Department of Orthopaedic SurgeryPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salin A","family":"Chakkalakal","sequence":"additional","affiliation":[{"name":"The Center for Research in FOP and Related DisordersPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"},{"name":"Department of Orthopaedic SurgeryPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"EnJun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory MedicinePerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J","family":"Caron","sequence":"additional","affiliation":[{"name":"The Center for Research in FOP and Related DisordersPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"},{"name":"Department of Orthopaedic SurgeryPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Center for Research in FOP and Related DisordersPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"},{"name":"Department of Orthopaedic SurgeryPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Kambayashi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory MedicinePerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick S","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of MedicinePerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"},{"name":"The Center for Research in FOP and Related DisordersPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"},{"name":"Department of Orthopaedic SurgeryPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen M","family":"Shore","sequence":"additional","affiliation":[{"name":"Department of GeneticsPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"},{"name":"The Center for Research in FOP and Related DisordersPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"},{"name":"Department of Orthopaedic SurgeryPerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,10,7]]},"reference":[{"issue":"3","key":"2024021014390034300_jbmr3304-bib-0001","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1002\/jbmr.2728","article-title":"The natural history of flare-ups 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