{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T12:02:36Z","timestamp":1785240156737,"version":"3.55.0"},"reference-count":46,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/100017962","name":"Jiangsu Commission of Health","doi-asserted-by":"publisher","award":["Z2020010"],"award-info":[{"award-number":["Z2020010"]}],"id":[{"id":"10.13039\/100017962","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pharmacology"],"published-print":{"date-parts":[[2022,8]]},"DOI":"10.1016\/j.ejphar.2022.175109","type":"journal-article","created":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T11:04:52Z","timestamp":1655723092000},"page":"175109","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":12,"special_numbering":"C","title":["Galunisertib attenuates progression of trauma-induced heterotopic ossification via blockage of Smad2\/3 signaling in mice"],"prefix":"10.1016","volume":"928","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8878-8220","authenticated-orcid":false,"given":"Dong","family":"Mao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Mi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyun","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjun","family":"Rui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ejphar.2022.175109_bib1","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1002\/stem.2515","article-title":"Scleraxis-lineage cells contribute to ectopic bone formation in muscle and tendon","volume":"35","author":"Agarwal","year":"2017","journal-title":"Stem Cell."},{"key":"10.1016\/j.ejphar.2022.175109_bib2","doi-asserted-by":"crossref","first-page":"3266","DOI":"10.1002\/stem.1847","article-title":"Tendon progenitor cells in injured tendons have strong chondrogenic potential: the CD105-negative subpopulation induces chondrogenic degeneration","volume":"32","author":"Asai","year":"2014","journal-title":"Stem Cell."},{"key":"10.1016\/j.ejphar.2022.175109_bib3","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1172\/JCI65416","article-title":"TGF-beta inhibition enhances chemotherapy action against triple-negative breast cancer","volume":"123","author":"Bhola","year":"2013","journal-title":"J. Clin. Invest."},{"key":"10.1016\/j.ejphar.2022.175109_bib4","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.bone.2017.08.023","article-title":"Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP)","volume":"109","author":"Brennan","year":"2018","journal-title":"Bone"},{"key":"10.1016\/j.ejphar.2022.175109_bib5","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.trsl.2017.06.004","article-title":"The traumatic bone: trauma-induced heterotopic ossification","volume":"186","author":"Dey","year":"2017","journal-title":"Transl. Res."},{"key":"10.1016\/j.ejphar.2022.175109_bib6","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1002\/jor.23808","article-title":"Post-traumatic heterotopic ossification: an old problem in need of new solutions","volume":"36","author":"Eisenstein","year":"2018","journal-title":"J. Orthop. Res."},{"key":"10.1016\/j.ejphar.2022.175109_bib7","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/s41467-018-03299-5","article-title":"Paracrine cellular senescence exacerbates biliary injury and impairs regeneration","volume":"9","author":"Ferreira-Gonzalez","year":"2018","journal-title":"Nat. Commun."},{"key":"10.1016\/j.ejphar.2022.175109_bib8","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1158\/0008-5472.CAN-14-0243","article-title":"Transforming growth factor-beta as a therapeutic target in hepatocellular carcinoma","volume":"74","author":"Giannelli","year":"2014","journal-title":"Cancer Res."},{"key":"10.1016\/j.ejphar.2022.175109_bib9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.aott.2017.11.008","article-title":"Appropriate excision time of heterotopic ossification in elbow caused by trauma","volume":"52","author":"He","year":"2018","journal-title":"Acta Orthop. Traumatol. Turcica"},{"key":"10.1016\/j.ejphar.2022.175109_bib10","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1002\/jcp.25955","article-title":"Leptin accelerates the pathogenesis of heterotopic ossification in rat tendon tissues via mTORC1 signaling","volume":"233","author":"Jiang","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"10.1016\/j.ejphar.2022.175109_bib11","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s00774-008-0879-8","article-title":"Skeletal metamorphosis in fibrodysplasia ossificans progressiva (FOP)","volume":"26","author":"Kaplan","year":"2008","journal-title":"J. Bone Miner. Metabol."},{"key":"10.1016\/j.ejphar.2022.175109_bib12","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1359\/jbmr.2000.15.11.2084","article-title":"Progressive osseous heteroplasia","volume":"15","author":"Kaplan","year":"2000","journal-title":"J. Bone Miner. Res."},{"key":"10.1016\/j.ejphar.2022.175109_bib13","doi-asserted-by":"crossref","DOI":"10.14309\/ctg.0000000000000056","article-title":"A phase 2 study of Galunisertib (TGF-beta1 receptor type I inhibitor) and Sorafenib in patients with advanced hepatocellular carcinoma","volume":"10","author":"Kelley","year":"2019","journal-title":"Clin. Transl. Gastroenterol."},{"key":"10.1016\/j.ejphar.2022.175109_bib14","doi-asserted-by":"crossref","DOI":"10.4172\/2161-0495.196","article-title":"Nonclinical safety evaluation of a transforming Growth factor \u03b2 receptor I kinase inhibitor in Fischer 344 rats and Beagle Dogs","volume":"4","author":"Kelly M Credill","year":"2014","journal-title":"J. Clin. Toxicol."},{"key":"10.1016\/j.ejphar.2022.175109_bib15","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.40814","article-title":"Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity","volume":"7","author":"Lees-Shepard","year":"2018","journal-title":"Elife"},{"key":"10.1016\/j.ejphar.2022.175109_bib16","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":"Lees-Shepard","year":"2018","journal-title":"Nat. Commun."},{"key":"10.1016\/j.ejphar.2022.175109_bib17","doi-asserted-by":"crossref","DOI":"10.1016\/j.bone.2020.115355","article-title":"TGF-beta1 plays a protective role in glucocorticoid-induced dystrophic calcification","volume":"136","author":"Li","year":"2020","journal-title":"Bone"},{"key":"10.1016\/j.ejphar.2022.175109_bib18","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1016\/j.jse.2019.08.013","article-title":"Celecoxib cannot inhibit the progression of initiated traumatic heterotopic ossification","volume":"28","author":"Li","year":"2019","journal-title":"J. Shoulder Elbow Surg."},{"key":"10.1016\/j.ejphar.2022.175109_bib19","doi-asserted-by":"crossref","DOI":"10.1016\/j.biopha.2020.110152","article-title":"Matrine attenuates heterotopic ossification by suppressing TGF-beta induced mesenchymal stromal cell migration and osteogenic differentiation","volume":"127","author":"Mao","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"10.1016\/j.ejphar.2022.175109_bib20","doi-asserted-by":"crossref","DOI":"10.1002\/jbm4.10172","article-title":"Heterotopic ossification: a comprehensive review","volume":"3","author":"Meyers","year":"2019","journal-title":"JBMR Plus"},{"key":"10.1016\/j.ejphar.2022.175109_bib21","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.bone.2016.01.004","article-title":"Inhibition of TGFbeta signaling decreases osteogenic differentiation of fibrodysplasia ossificans progressiva fibroblasts in a novel in vitro model of the disease","volume":"84","author":"Micha","year":"2016","journal-title":"Bone"},{"key":"10.1016\/j.ejphar.2022.175109_bib22","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1097\/BOT.0b013e3182724624","article-title":"Heterotopic ossification in orthopaedic trauma","volume":"26","author":"Nauth","year":"2012","journal-title":"J. Orthop. Trauma"},{"key":"10.1016\/j.ejphar.2022.175109_bib23","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1111\/j.1365-2613.2012.00829.x","article-title":"Heterotopic mineralization (ossification or calcification) in tendinopathy or following surgical tendon trauma","volume":"93","author":"O'Brien","year":"2012","journal-title":"Int. J. Exp. Pathol."},{"key":"10.1016\/j.ejphar.2022.175109_bib24","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1002\/jor.22404","article-title":"Tendon mineralization is accelerated bilaterally and creep of contralateral tendons is increased after unilateral needle injury of murine achilles tendons","volume":"31","author":"O'Brien","year":"2013","journal-title":"J. Orthop. Res."},{"key":"10.1016\/j.ejphar.2022.175109_bib25","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.bone.2016.06.014","article-title":"Targeted stimulation of retinoic acid receptor-gamma mitigates the formation of heterotopic ossification in an established blast-related traumatic injury model","volume":"90","author":"Pavey","year":"2016","journal-title":"Bone"},{"key":"10.1016\/j.ejphar.2022.175109_bib26","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.2106\/JBJS.N.01056","article-title":"Heterotopic ossification: Basic-Science principles and clinical correlates","volume":"97","author":"Ranganathan","year":"2015","journal-title":"J. Bone Joint Surg. Am."},{"key":"10.1016\/j.ejphar.2022.175109_bib27","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1097\/CORR.0000000000000594","article-title":"Failure of indomethacin and radiation to prevent blast-induced heterotopic ossification in a Sprague-Dawley rat model","volume":"477","author":"Robertson","year":"2019","journal-title":"Clin. Orthop. Relat. Res."},{"key":"10.1016\/j.ejphar.2022.175109_bib28","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/s10637-014-0192-4","article-title":"Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-beta receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer","volume":"33","author":"Rodon","year":"2015","journal-title":"Invest. N. Drugs"},{"key":"10.1016\/j.ejphar.2022.175109_bib29","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1158\/1078-0432.CCR-14-1380","article-title":"First-in-human dose study of the novel transforming growth factor-beta receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma","volume":"21","author":"Rodon","year":"2015","journal-title":"Clin. Cancer Res. : an official journal of the American Association for Cancer Research"},{"key":"10.1016\/j.ejphar.2022.175109_bib30","doi-asserted-by":"crossref","first-page":"6976","DOI":"10.1158\/1078-0432.CCR-19-1338","article-title":"Phase II study of the ALK5 inhibitor Galunisertib in very low-, low-, and intermediate-risk myelodysplastic Syndromes","volume":"25","author":"Santini","year":"2019","journal-title":"Clin. Cancer Res. : an official journal of the American Association for Cancer Research"},{"key":"10.1016\/j.ejphar.2022.175109_bib31","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/nm.2334","article-title":"Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists","volume":"17","author":"Shimono","year":"2011","journal-title":"Nat. Med."},{"key":"10.1016\/j.ejphar.2022.175109_bib32","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.bone.2008.05.013","article-title":"Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva (FOP)","volume":"43","author":"Shore","year":"2008","journal-title":"Bone"},{"key":"10.1016\/j.ejphar.2022.175109_bib33","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":"10.1016\/j.ejphar.2022.175109_bib34","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/s41467-019-14172-4","article-title":"Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing","volume":"11","author":"Sorkin","year":"2020","journal-title":"Nat. Commun."},{"key":"10.1016\/j.ejphar.2022.175109_bib35","doi-asserted-by":"crossref","DOI":"10.1016\/j.bone.2020.115517","article-title":"Small molecule inhibition of non-canonical (TAK1-mediated) BMP signaling results in reduced chondrogenic ossification and heterotopic ossification in a rat model of blast-associated combat-related lower limb trauma","volume":"139","author":"Strong","year":"2020","journal-title":"Bone"},{"key":"10.1016\/j.ejphar.2022.175109_bib36","doi-asserted-by":"crossref","first-page":"7840","DOI":"10.1073\/pnas.1522054113","article-title":"Gene targeting of the transcription factor Mohawk in rats causes heterotopic ossification of Achilles tendon via failed tenogenesis","volume":"113","author":"Suzuki","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.ejphar.2022.175109_bib37","doi-asserted-by":"crossref","DOI":"10.3390\/biom10030487","article-title":"TGF-Beta signaling","volume":"10","author":"Tzavlaki","year":"2020","journal-title":"Biomolecules"},{"key":"10.1016\/j.ejphar.2022.175109_bib38","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":"van Dinther","year":"2010","journal-title":"J. Bone Miner. Res."},{"key":"10.1016\/j.ejphar.2022.175109_bib39","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/s41467-018-02988-5","article-title":"Inhibition of overactive TGF-beta attenuates progression of heterotopic ossification in mice","volume":"9","author":"Wang","year":"2018","journal-title":"Nat. Commun."},{"key":"10.1016\/j.ejphar.2022.175109_bib40","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1172\/JCI96186","article-title":"Aberrant TGF-beta activation in bone tendon insertion induces enthesopathy-like disease","volume":"128","author":"Wang","year":"2018","journal-title":"J. Clin. Invest."},{"key":"10.1016\/j.ejphar.2022.175109_bib41","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1007\/s10637-020-00910-9","article-title":"Phase 1b\/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma","volume":"38","author":"Wick","year":"2020","journal-title":"Invest. N. Drugs"},{"key":"10.1016\/j.ejphar.2022.175109_bib42","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1038\/nm.1888","article-title":"BMP type I receptor inhibition reduces heterotopic [corrected] ossification","volume":"14","author":"Yu","year":"2008","journal-title":"Nat. Med."},{"key":"10.1016\/j.ejphar.2022.175109_bib43","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1002\/jor.21485","article-title":"BMP-2 mediates PGE(2) -induced reduction of proliferation and osteogenic differentiation of human tendon stem cells","volume":"30","author":"Zhang","year":"2012","journal-title":"J. Orthop. Res."},{"key":"10.1016\/j.ejphar.2022.175109_bib44","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.bbrc.2014.06.058","article-title":"Effects of celecoxib on proliferation and tenocytic differentiation of tendon-derived stem cells","volume":"450","author":"Zhang","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.ejphar.2022.175109_bib45","doi-asserted-by":"crossref","first-page":"7030","DOI":"10.18632\/aging.103060","article-title":"betaig-h3 enhances chondrogenesis via promoting mesenchymal condensation in rat Achilles tendon heterotopic ossification model","volume":"12","author":"Zhang","year":"2020","journal-title":"Aging (Albany NY)"},{"key":"10.1016\/j.ejphar.2022.175109_bib46","doi-asserted-by":"crossref","first-page":"5428","DOI":"10.1111\/jcmm.15240","article-title":"Heterotopic ossification of tendon and ligament","volume":"24","author":"Zhang","year":"2020","journal-title":"J. Cell Mol. Med."}],"container-title":["European Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0014299922003703?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0014299922003703?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T04:17:19Z","timestamp":1762143439000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0014299922003703"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8]]},"references-count":46,"alternative-id":["S0014299922003703"],"URL":"https:\/\/doi.org\/10.1016\/j.ejphar.2022.175109","relation":{},"ISSN":["0014-2999"],"issn-type":[{"value":"0014-2999","type":"print"}],"subject":[],"published":{"date-parts":[[2022,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Galunisertib attenuates progression of trauma-induced heterotopic ossification via blockage of Smad2\/3 signaling in mice","name":"articletitle","label":"Article Title"},{"value":"European Journal of Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejphar.2022.175109","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2022 Elsevier B.V. All rights reserved.","name":"copyright","label":"Copyright"}],"article-number":"175109"}}