{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T13:46:51Z","timestamp":1790344011975,"version":"4.1.0"},"reference-count":87,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T00:00:00Z","timestamp":1705017600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodic yet cumulative heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. FOP arises from missense mutations in Activin Receptor type I (ACVR1), a type I bone morphogenetic protein (BMP) receptor. Although initial findings implicated constitutive activity of FOP-variant ACVR1 (ACVR1FOP) and\/or hyperactivation by BMPs, it was later shown that HO in FOP requires activation of ACVR1FOP by Activin A. Inhibition of Activin A completely prevents HO in FOP mice, indicating that Activin A is an obligate driver of HO in FOP, and excluding a key role for BMPs in this process. This discovery led to the clinical development of garetosmab, an investigational antibody that blocks Activin A. In a phase 2 trial, garetosmab inhibited new heterotopic bone lesion formation in FOP patients. In contrast, antibodies to ACVR1 activate ACVR1FOP and promote HO in FOP mice. Beyond their potential clinical relevance, these findings have enhanced our understanding of FOP\u2019s pathophysiology, leading to the identification of fibroadipogenic progenitors as the cells that form HO, and the discovery of non-signaling complexes between Activin A and wild type ACVR1 and their role in tempering HO, and are also starting to inform biological processes beyond FOP.<\/jats:p>","DOI":"10.3390\/biom14010101","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T07:47:16Z","timestamp":1705045636000},"page":"101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["How Activin A Became a Therapeutic Target in Fibrodysplasia Ossificans Progressiva"],"prefix":"10.3390","volume":"14","author":[{"given":"Dushyanth","family":"Srinivasan","sequence":"first","affiliation":[{"name":"Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Arostegui","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erich J.","family":"Goebel","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0484-1969","authenticated-orcid":false,"given":"Kaitlin N.","family":"Hart","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7250-2913","authenticated-orcid":false,"given":"Senem","family":"Aykul","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John B.","family":"Lees-Shepard","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Idone","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1103-6087","authenticated-orcid":false,"given":"Sarah J.","family":"Hatsell","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6508-8942","authenticated-orcid":false,"given":"Aris N.","family":"Economides","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.2106\/00004623-199302000-00008","article-title":"The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients","volume":"75","author":"Cohen","year":"1993","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1159\/000365770","article-title":"Fibrodysplasia ossificans progressiva: Clinical course, genetic mutations and genotype-phenotype correlation","volume":"5","author":"Huning","year":"2014","journal-title":"Mol. Syndromol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s13023-019-1068-7","article-title":"Natural history of fibrodysplasia ossificans progressiva: Cross-sectional analysis of annotated baseline phenotypes","volume":"14","author":"Pignolo","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/S0278-2391(10)80212-5","article-title":"Failure of surgery and isotretinoin to relieve jaw immobilization in fibrodysplasia ossificans progressiva: Report of two cases","volume":"48","author":"Crofford","year":"1990","journal-title":"J. Oral. Maxillofac. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"570","DOI":"10.3389\/fendo.2020.00570","article-title":"When Limb Surgery Has Become the Only Life-Saving Therapy in FOP: A Case Report and Systematic Review of the Literature","volume":"11","author":"Botman","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1002\/jbmr.2728","article-title":"The Natural History of Flare-Ups in Fibrodysplasia Ossificans Progressiva (FOP): A Comprehensive Global Assessment","volume":"31","author":"Pignolo","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1016\/j.gim.2022.08.013","article-title":"The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study","volume":"24","author":"Pignolo","year":"2022","journal-title":"Genet. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1126\/science.150.3698.893","article-title":"Bone: Formation by autoinduction","volume":"150","author":"Urist","year":"1965","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.bone.2017.07.024","article-title":"Heterotopic bone induction via BMP signaling: Potential therapeutic targets for fibrodysplasia ossificans progressiva","volume":"109","author":"Katagiri","year":"2018","journal-title":"Bone"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1056\/NEJM199608223350804","article-title":"Overexpression of an Osteogenic Morphogen in Fibrodysplasia Ossificans Progressiva","volume":"335","author":"Shafritz","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1097\/00003086-200303000-00044","article-title":"Bone morphogenetic protein-4 regulation in fibrodysplasia ossificans progressiva","volume":"408","author":"Olmsted","year":"2003","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/S0002-9440(10)63372-X","article-title":"Transgenic mice overexpressing BMP4 develop a fibrodysplasia ossificans progressiva (FOP)-like phenotype","volume":"165","author":"Kan","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.2106\/00004623-200312000-00010","article-title":"In vivo somatic cell gene transfer of an engineered Noggin mutein prevents BMP4-induced heterotopic ossification","volume":"85","author":"Glaser","year":"2003","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1385\/BMM:3:3-4:195","article-title":"The fibrodysplasia ossificans progressiva lesion","volume":"3","author":"Pignolo","year":"2005","journal-title":"Clin. Rev. Bone Miner. Metab."},{"key":"ref_15","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."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1002\/jbmr.2385","article-title":"The type I BMP receptor ACVR1\/ALK2 is required for chondrogenesis during development","volume":"30","author":"Rigueur","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/humu.20868","article-title":"Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1","volume":"30","author":"Kaplan","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1002\/j.1460-2075.1995.tb07214.x","article-title":"GS domain mutations that constitutively activate T beta RI, the downstream signaling component in the TGF-beta receptor complex","volume":"14","author":"Wieser","year":"1995","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1002\/dvg.20201","article-title":"Generation of a mouse with conditionally activated signaling through the BMP receptor, ALK2","volume":"44","author":"Fukuda","year":"2006","journal-title":"Genesis"},{"key":"ref_20","first-page":"3462","article-title":"The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization","volume":"119","author":"Shen","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_21","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."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1359\/jbmr.091110","article-title":"ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation","volume":"25","author":"Dinther","year":"2010","journal-title":"J. Bone Miner. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/1750-1172-6-80","article-title":"Fibrodysplasia Ossificans Progressiva: Clinical and Genetic Aspects","volume":"6","author":"Pignolo","year":"2011","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_24","first-page":"113","article-title":"Monitoring and Management of Fibrodysplasia Ossificans Progressiva: Current Perspectives","volume":"14","author":"Smilde","year":"2022","journal-title":"Orthop. Res. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4224","DOI":"10.1182\/blood-2011-03-339952","article-title":"Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice","volume":"118","author":"Steinbicker","year":"2011","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/bs.vh.2019.01.004","article-title":"Hepcidin and the BMP-SMAD pathway: An unexpected liaison","volume":"110","author":"Silvestri","year":"2019","journal-title":"Vitam. Horm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/ng.130","article-title":"Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)","volume":"40","author":"Finberg","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3392","DOI":"10.1182\/blood-2017-03-773481","article-title":"A new form of IRIDA due to combined heterozygous mutations of TMPRSS6 and ACVR1A encoding the BMP receptor ALK2","volume":"129","author":"Pagani","year":"2017","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"303ra137","DOI":"10.1126\/scitranslmed.aac4358","article-title":"ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A","volume":"7","author":"Hatsell","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15438","DOI":"10.1073\/pnas.1510540112","article-title":"Neofunction of ACVR1 in fibrodysplasia ossificans progressiva","volume":"112","author":"Hino","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1002\/jcph.1638","article-title":"Pharmacokinetics and Pharmacodynamics of Garetosmab (Anti-Activin A): Results From a First-in-Human Phase 1 Study","volume":"60","author":"Vanhoutte","year":"2020","journal-title":"J. Clin. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1038\/s41591-023-02561-8","article-title":"Garetosmab in fibrodysplasia ossificans progressiva: A randomized, double-blind, placebo-controlled phase 2 trial","volume":"29","author":"Pignolo","year":"2023","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cappato, S., Giacopelli, F., Ravazzolo, R., and Bocciardi, R. (2018). The Horizon of a Therapy for Rare Genetic Diseases: A \u201cDruggable\u201d Future for Fibrodysplasia Ossificans Progressiva. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19040989"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kitoh, H. (2020). Clinical Aspects and Current Therapeutic Approaches for FOP. Biomedicines, 8.","DOI":"10.3390\/biomedicines8090325"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1002\/jbmr.1637","article-title":"An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva","volume":"27","author":"Chakkalakal","year":"2012","journal-title":"J. Bone Miner. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/nbt811","article-title":"A directional strategy for monitoring Cre-mediated recombination at the cellular level in the mouse","volume":"21","author":"Schnutgen","year":"2003","journal-title":"Nat. Biotechnol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1002\/jbmr.3235","article-title":"The Expansion of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva Is Activin A-Dependent","volume":"32","author":"Upadhyay","year":"2017","journal-title":"J. Bone Miner. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21037","DOI":"10.1074\/jbc.M110.114959","article-title":"Characterization of the ligand binding functionality of the extracellular domain of activin receptor type IIb","volume":"285","author":"Sako","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.cytogfr.2020.09.003","article-title":"Receptor binding competition: A paradigm for regulating TGF-beta family action","volume":"57","author":"Sundan","year":"2021","journal-title":"Cytokine Growth Factor. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.mce.2011.10.009","article-title":"The roles of activin A and its binding protein, follistatin, in inflammation and tissue repair","volume":"359","author":"Hardy","year":"2012","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/0092-8674(93)90488-C","article-title":"Identification of human activin and TGF\u03b2 type I receptors that form heteromeric kinase complexes with type II receptors","volume":"75","author":"Attisano","year":"1993","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1126\/science.8235612","article-title":"Determination of type I receptor specificity by the type II receptors for TGF-beta or activin","volume":"262","author":"Ebner","year":"1993","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"11242","DOI":"10.1073\/pnas.90.23.11242","article-title":"Cloning and characterization of a transmembrane serine kinase that acts as an activin type I receptor","volume":"90","author":"Tsuchida","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"15153","DOI":"10.1038\/ncomms15153","article-title":"Activin A more prominently regulates muscle mass in primates than does GDF8","volume":"8","author":"Latres","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e54582","DOI":"10.7554\/eLife.54582","article-title":"Activin A forms a non-signaling complex with ACVR1 and type II Activin\/BMP receptors via its finger 2 tip loop","volume":"9","author":"Aykul","year":"2020","journal-title":"eLife"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"366ra163","DOI":"10.1126\/scitranslmed.aaf1090","article-title":"Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification","volume":"8","author":"Dey","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/s41467-018-02872-2","article-title":"Activin-dependent signaling in fibro\/adipogenic progenitors causes fibrodysplasia ossificans progressiva","volume":"9","author":"Yamamoto","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e1774","DOI":"10.1002\/mgg3.1774","article-title":"A case of Fibrodysplasia Ossificans Progressiva associated with a novel variant of the ACVR1 gene","volume":"9","author":"Cappato","year":"2021","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2960","DOI":"10.1038\/s41467-023-38746-5","article-title":"A blocking monoclonal antibody reveals dimerization of intracellular domains of ALK2 associated with genetic disorders","volume":"14","author":"Katagiri","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e153792","DOI":"10.1172\/JCI153792","article-title":"Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1","volume":"132","author":"Aykul","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e153795","DOI":"10.1172\/JCI153795","article-title":"An anti-ACVR1 antibody exacerbates heterotopic ossification by fibro-adipogenic progenitors in fibrodysplasia ossificans progressiva mice","volume":"132","author":"Stoessel","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/370341a0","article-title":"Mechanism of activation of the TGF-beta receptor","volume":"370","author":"Wrana","year":"1994","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1128\/MCB.01595-12","article-title":"Constitutively active ALK2 receptor mutants require type II receptor cooperation","volume":"33","author":"Bagarova","year":"2013","journal-title":"Mol. Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"eaav5183","DOI":"10.1126\/scisignal.aav5183","article-title":"Specificity, versatility, and control of TGF-beta family signaling","volume":"12","author":"Derynck","year":"2019","journal-title":"Sci. Signal"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1091\/mbc.11.3.1023","article-title":"Bone morphogenetic protein receptor complexes on the surface of live cells: A new oligomerization mode for serine\/threonine kinase receptors","volume":"11","author":"Gilboa","year":"2000","journal-title":"Mol. Biol. Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1210\/me.2004-0079","article-title":"Receptor internalization-independent activation of Smad2 in activin signaling","volume":"18","author":"Zhou","year":"2004","journal-title":"Mol. Endocrinol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1016\/j.cellsig.2011.04.004","article-title":"Homomeric and heteromeric complexes among TGF-beta and BMP receptors and their roles in signaling","volume":"23","author":"Ehrlich","year":"2011","journal-title":"Cell Signal"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1038\/nm.2252","article-title":"Conversion of vascular endothelial cells into multipotent stem-like cells","volume":"16","author":"Medici","year":"2010","journal-title":"Nat. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1002\/dvdy.21179","article-title":"Generation of transgenic tendon reporters, ScxGFP and ScxAP, using regulatory elements of the scleraxis gene","volume":"236","author":"Pryce","year":"2007","journal-title":"Dev. Dyn."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.stem.2012.02.003","article-title":"Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration","volume":"10","author":"Park","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.stem.2019.11.004","article-title":"Hic1 Defines Quiescent Mesenchymal Progenitor Subpopulations with Distinct Functions and Fates in Skeletal Muscle Regeneration","volume":"25","author":"Scott","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/ncb2015","article-title":"Muscle injury activates resident fibro\/adipogenic progenitors that facilitate myogenesis","volume":"12","author":"Joe","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3654","DOI":"10.1242\/jcs.086629","article-title":"Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle","volume":"124","author":"Uezumi","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Oishi, T., Uezumi, A., Kanaji, A., Yamamoto, N., Yamaguchi, A., Yamada, H., and Tsuchida, K. (2013). Osteogenic differentiation capacity of human skeletal muscle-derived progenitor cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056641"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Penton, C.M., Thomas-Ahner, J.M., Johnson, E.K., McAllister, C., and Montanaro, F. (2013). Muscle side population cells from dystrophic or injured muscle adopt a fibro-adipogenic fate. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054553"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1002\/jbmr.1562","article-title":"Multipotent progenitors resident in the skeletal muscle interstitium exhibit robust BMP-dependent osteogenic activity and mediate heterotopic ossification","volume":"27","author":"Wosczyna","year":"2012","journal-title":"J. Bone Miner. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1002\/jbmr.4020","article-title":"Murine Tissue-Resident PDGFRalpha+ Fibro-Adipogenic Progenitors Spontaneously Acquire Osteogenic Phenotype in an Altered Inflammatory Environment","volume":"35","author":"Eisner","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1002\/stem.1082","article-title":"Functionally convergent white adipogenic progenitors of different lineages participate in a diffused system supporting tissue regeneration","volume":"30","author":"Lemos","year":"2012","journal-title":"Stem Cells"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1038\/s41556-019-0417-z","article-title":"A Tppp3+Pdgfra+ tendon stem cell population contributes to regeneration and reveals a shared role for PDGF signalling in regeneration and fibrosis","volume":"21","author":"Harvey","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3797","DOI":"10.1242\/dev.124.19.3797","article-title":"The ALK-2 and ALK-4 activin receptors transduce distinct mesoderm-inducing signals during early Xenopus development but do not co-operate to establish thresholds","volume":"124","author":"Armes","year":"1997","journal-title":"Development"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"12938","DOI":"10.1073\/pnas.94.24.12938","article-title":"Smad8 mediates the signaling of the ALK-2 [corrected] receptor serine kinase","volume":"94","author":"Chen","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"25628","DOI":"10.1074\/jbc.273.40.25628","article-title":"Specific Activation of Smad1 Signaling Pathways by the BMP7 Type I Receptor, ALK2","volume":"273","author":"Hoodless","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1002\/(SICI)1097-4652(199908)180:2<141::AID-JCP1>3.0.CO;2-I","article-title":"Functional antagonism between activin and osteogenic protein-1 in human embryonal carcinoma cells","volume":"180","author":"Piek","year":"1999","journal-title":"J. Cell Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"10792","DOI":"10.1074\/jbc.M115.713487","article-title":"Transforming Growth Factor-beta Family Ligands Can Function as Antagonists by Competing for Type II Receptor Binding","volume":"291","author":"Aykul","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"15505","DOI":"10.1073\/pnas.1906253116","article-title":"Structural characterization of an activin class ternary receptor complex reveals a third paradigm for receptor specificity","volume":"116","author":"Goebel","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1002\/jbmr.4617","article-title":"Overexpression of Wild-Type ACVR1 in Fibrodysplasia Ossificans Progressiva Mice Rescues Perinatal Lethality and Inhibits Heterotopic Ossification","volume":"37","author":"Yamamoto","year":"2022","journal-title":"J. Bone Miner. Res."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Katagiri, T., Tsukamoto, S., and Kuratani, M. (2021). Accumulated Knowledge of Activin Receptor-Like Kinase 2 (ALK2)\/Activin A Receptor, Type 1 (ACVR1) as a Target for Human Disorders. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070736"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Ventura, F., Williams, E., Ikeya, M., Bullock, A.N., Ten Dijke, P., Goumans, M.J., and Sanchez-Duffhues, G. (2021). Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva. Biomedicines, 9.","DOI":"10.3390\/biomedicines9020213"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Valer, J.A., Sanchez-de-Diego, C., Pimenta-Lopes, C., Rosa, J.L., and Ventura, F. (2019). ACVR1 Function in Health and Disease. Cells, 8.","DOI":"10.3390\/cells8111366"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Lin, H., Shi, F., Gao, J., and Hua, P. (2019). The role of Activin A in fibrodysplasia ossificans progressiva: A prominent mediator. Biosci. Rep., 39.","DOI":"10.1042\/BSR20190377"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1111\/bcp.13823","article-title":"Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva","volume":"85","author":"Wentworth","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"331","DOI":"10.3803\/EnM.2018.33.3.331","article-title":"Recent Topics in Fibrodysplasia Ossificans Progressiva","volume":"33","author":"Katagiri","year":"2018","journal-title":"Endocrinol. Metab."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.bone.2017.11.014","article-title":"Activin A amplifies dysregulated BMP signaling and induces chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP)","volume":"109","author":"Wang","year":"2018","journal-title":"Bone"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Xie, C., Jiang, W., Lacroix, J.J., Luo, Y., and Hao, J. (2020). Insight into Molecular Mechanism for Activin A-Induced Bone Morphogenetic Protein Signaling. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186498"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e106317","DOI":"10.15252\/embj.2020106317","article-title":"Pathogenic ACVR1(R206H) activation by Activin A-induced receptor clustering and autophosphorylation","volume":"40","author":"Ramachandran","year":"2021","journal-title":"EMBO J."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e10821","DOI":"10.1002\/jbm4.10821","article-title":"Palovarotene Action Against Heterotopic Ossification Includes a Reduction of Local Participating Activin A-Expressing Cell Populations","volume":"7","author":"Mundy","year":"2023","journal-title":"JBMR Plus"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"5330","DOI":"10.1074\/jbc.M102750200","article-title":"The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways","volume":"277","author":"Nohe","year":"2002","journal-title":"J. Biol. Chem."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/1\/101\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:45:30Z","timestamp":1760103930000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/1\/101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,12]]},"references-count":87,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["biom14010101"],"URL":"https:\/\/doi.org\/10.3390\/biom14010101","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,12]]}}}