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New therapies are urgently needed. Activin A, a member of the transforming growth factor \u03b2 (TGF\u03b2) superfamily, has been suggested to stimulate proliferation and invasion of osteosarcoma cells in vitro, thus representing a potential therapeutic target. In this study, inhibition of the activin receptor signaling pathway was explored as a therapy for osteosarcoma. In a murine intratibial osteosarcoma xenograft model, two types of inhibitors were tested: (a) a soluble activin type IIA decoy receptor (ActRIIA\u2010mFc), or (b) a modified variant of follistatin (FST<jats:sub>\u0394HBS<\/jats:sub>\u2010hFc), either alone or in combination with a bisphosphonate. Both inhibitors reduced primary tumor development by nearly 50% compared to vehicle treatment. When ActRIIA\u2010mFc was combined with bisphosphonate, the effect on tumor size became even more pronounced (78% reduction vs. vehicle). Moreover, FST<jats:sub>\u0394HBS<\/jats:sub>\u2010hFc increased body weight in the face of tumor progression (14% increase vs. vehicle), and ActRIIA\u2010mFc reduced the number of lung metastases when combined with bisphosphonate. The present study demonstrates a novel approach to treating osteosarcoma and encourages further investigation of inhibition of the activin receptor signaling pathway as an intervention against the disease.<\/jats:p>","DOI":"10.1002\/cam4.3581","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T13:29:40Z","timestamp":1605187780000},"page":"286-296","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Inhibition of the activin receptor signaling pathway: A novel intervention against osteosarcoma"],"prefix":"10.1002","volume":"10","author":[{"given":"Daniela","family":"Meier","sequence":"first","affiliation":[{"name":"Department of Orthopedics Balgrist University Hospital Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9261-8753","authenticated-orcid":false,"given":"Andreas","family":"Lodberg","sequence":"additional","affiliation":[{"name":"Department of Biomedicine Aarhus University Aarhus Denmark"},{"name":"Department of Pulmonary Medicine Aarhus University Hospital Aarhus Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6013-0355","authenticated-orcid":false,"given":"Ana","family":"Gvozdenovic","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Balgrist University Hospital Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"Laboratory for Animal Model Pathology Institute of Veterinary Pathology, University of Zurich Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga","family":"Neklyudova","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Balgrist University Hospital Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter","family":"Born","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Balgrist University Hospital Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruno","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Balgrist University Hospital Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Eijken","sequence":"additional","affiliation":[{"name":"Department of Renal Medicine Aarhus University Hospital Aarhus Denmark"},{"name":"Department of Clinical Immunology Aarhus University Hospital Aarhus Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1695-1700","authenticated-orcid":false,"given":"Sander","family":"M. 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