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Current anabolic treatments primarily rely on biologics, which are costly and require inconvenient administration. Identifying regulators of osteoblastogenesis that are amenable to small-molecule targeting is essential for developing more accessible therapies. Through an unbiased kinome-wide RNAi screen in primary murine calvarial osteoblasts, we identified the AXL receptor tyrosine kinase (Axl) as a negative regulator of osteoblast differentiation. Axl is most highly expressed in undifferentiated and early differentiated osteoblasts, with a rapid decline in expression during osteoblast maturation. siRNA-mediated knockdown of Axl or pharmacological inhibition with the small molecule BGB324 significantly enhanced osteoblast differentiation and mineralization in vitro. In mice, BGB324 treatment significantly increased bone mass by promoting bone formation. Mechanistically, Axl knockdown or inhibition upregulated interferon-stimulated gene 15\n                    <jats:italic>(Isg15)<\/jats:italic>\n                    , while\n                    <jats:italic>Isg15<\/jats:italic>\n                    knockdown impaired osteoblast differentiation and enhanced Erk phosphorylation, leading to increased expression of osteoblast-specific genes. Consistently, double knockdown experiments demonstrated that simultaneous loss of\n                    <jats:italic>Axl<\/jats:italic>\n                    with either\n                    <jats:italic>Isg15<\/jats:italic>\n                    or\n                    <jats:italic>Mapk1<\/jats:italic>\n                    , but not other interferon-related genes, reversed the\n                    <jats:italic>Axl<\/jats:italic>\n                    knockdown-induced increase in osteoblast differentiation, reinforcing their mechanistic involvement. Collectively, our study identifies\n                    <jats:italic>Axl<\/jats:italic>\n                    as a promising therapeutic target for osteoporosis and other bone-related disorders.\n                  <\/jats:p>","DOI":"10.1038\/s41413-026-00554-0","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T11:56:38Z","timestamp":1783338998000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhibition of AXL receptor tyrosine kinase increases osteoblast function and bone mass"],"prefix":"10.1038","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9012-4039","authenticated-orcid":false,"given":"Mubashir","family":"Ahmad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9193-9369","authenticated-orcid":false,"given":"Christoph","family":"K\u00f6lbl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irfana","family":"Jan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann-Kristin","family":"Dorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burak","family":"\u00d6zkan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Olde Heuvel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilay","family":"Yilmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessa","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Vujic Spasic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin Thilo","family":"Kr\u00fcger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6244-4975","authenticated-orcid":false,"given":"Sooyeon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Roselli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4782-1979","authenticated-orcid":false,"given":"Anita","family":"Ignatius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3691-275X","authenticated-orcid":false,"given":"Jan","family":"Tuckermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"554_CR1","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.jsbmb.2013.09.008","volume":"142","author":"SH Tella","year":"2014","unstructured":"Tella, S. 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