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Mesenchymal stem cells (MSCs) play a central role in HO by differentiating into osteoblasts through endochondral or intramembranous ossification, while alternative fates such as adipogenesis are suppressed. In this study, we investigated the effects of two commonly used antispastic drugs, baclofen and tizanidine, on MSC differentiation under adipogenic and inflammatory conditions in vitro. (2) Mouse C3H10T1\/2 MSCs were cultured and induced toward adipogenesis in the presence of baclofen or tizanidine, and inflammatory stimuli (Interleukin-1\u03b2 or lipopolysaccharides) were applied where indicated. Gene expressions of adipogenic and osteochondrogenic markers were assessed by RT-qPCR, while osteopontin protein levels were quantified by Simple Western. (3) Baclofen treatment significantly inhibited adipogenic gene expression and promoted osteochondrogenic markers and osteopontin protein under basal conditions, whereas tizanidine had minimal effects. Under inflammatory conditions, baclofen partially suppressed adipogenesis but did not strongly induce osteochondrogenesis. (4) These findings indicate that baclofen can directly modulate MSC fate, potentially contributing to HO risk, while tizanidine may offer a safer alternative for spasticity management in patients at risk of ectopic bone formation.<\/jats:p>","DOI":"10.3390\/ijms27062783","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T08:54:37Z","timestamp":1773910477000},"page":"2783","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Baclofen Promotes Osteochondrogenic Commitment of Mesenchymal Stem Cells: Implications for Heterotopic Ossification Risk"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9280-369X","authenticated-orcid":false,"given":"Mar\u00eda","family":"Crugeiras-Sampedro","sequence":"first","affiliation":[{"name":"Musculoskeletal Pathology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Clinical Hospital, Servizo Galego de Saude (SERGAS), 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorena","family":"Zas-Veiga","sequence":"additional","affiliation":[{"name":"Musculoskeletal Pathology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Clinical Hospital, Servizo Galego de Saude (SERGAS), 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"Pi\u00f1eiro-Ramil","sequence":"additional","affiliation":[{"name":"Musculoskeletal Pathology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Clinical Hospital, Servizo Galego de Saude (SERGAS), 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9s","family":"Pazos-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Musculoskeletal Pathology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Clinical Hospital, Servizo Galego de Saude (SERGAS), 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ver\u00f3nica","family":"L\u00f3pez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Musculoskeletal Pathology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Clinical Hospital, Servizo Galego de Saude (SERGAS), 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0143-1323","authenticated-orcid":false,"given":"Alberto","family":"Jorge-Mora","sequence":"additional","affiliation":[{"name":"Musculoskeletal Pathology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Clinical Hospital, Servizo Galego de Saude (SERGAS), 15706 Santiago de Compostela, Spain"},{"name":"Traumatology and Orthopedics Service, A Coru\u00f1a University Clinical Hospital, Servizo Galego de Saude (SERGAS), 15006 A Coru\u00f1a, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5830-0960","authenticated-orcid":false,"given":"Ana","family":"Alonso-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Musculoskeletal Pathology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Clinical Hospital, Servizo Galego de Saude (SERGAS), 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1309-1023","authenticated-orcid":false,"given":"Rodolfo","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Musculoskeletal Pathology Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago University Clinical Hospital, Servizo Galego de Saude (SERGAS), 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105821","DOI":"10.1016\/j.clineuro.2020.105821","article-title":"Factors Associated with Higher Rates of Heterotopic Ossification after Spinal Cord Injury: A Systematic Review and Meta-Analysis","volume":"195","author":"Yolcu","year":"2020","journal-title":"Clin. 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