{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T13:01:55Z","timestamp":1793278915681,"version":"4.5.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2007,11,1]],"date-time":"2007-11-01T00:00:00Z","timestamp":1193875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Several lines of evidence suggest that imatinib may affect skeletal tissue. We show that inhibition by imatinib of PDGFR signaling in osteoblasts activates osteoblast differentiation and inhibits osteoblast proliferation and that imatinib inhibits osteoclastogenesis by both stromal cell-dependent and direct effects on osteoclast precursors.<\/jats:p>\n               <jats:p>Introduction: Imatinib mesylate, an orally active inhibitor of the c-abl, c-kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, is in clinical use for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal cell tumors. Interruption of both c-kit and c-abl signaling in mice induces osteopenia, suggesting that imatinib might have adverse effects on the skeleton. However, biochemical markers of bone formation increase in patients with CML starting imatinib therapy, whereas bone resorption is unchanged, despite secondary hyperparathyroidism. We assessed the actions of imatinib on bone cells in vitro to study the cellular and molecular mechanism(s) underlying the skeletal effects we observed in imatinib-treated patients.<\/jats:p>\n               <jats:p>Materials and Methods: Osteoblast differentiation was assessed using a mineralization assay, proliferation by [3H]thymidine incorporation, and apoptosis by a TUNEL assay. Osteoclastogenesis was assessed using murine bone marrow cultures and RAW 264.7 cells. RT and multiplex PCR were performed on RNA prepared from human bone marrow samples, osteoblastic cells, and murine bone marrow cultures. Osteoprotegerin was measured by ELISA.<\/jats:p>\n               <jats:p>Results: The molecular targets of imatinib are expressed in bone cells. In vitro, imatinib increases osteoblast differentiation and prevents PDGF-induced inhibition of this process. Imatinib inhibits proliferation of osteoblast-like cells induced by serum and PDGF. In murine bone marrow cultures, imatinib inhibits osteoclastogenesis stimulated by 1,25-dihydroxyvitamin D3 and partially inhibits osteoclastogenesis induced by RANKL and macrophage-colony stimulating factor. Imatinib partially inhibited osteoclastogenesis in RANKL-stimulated RAW-264.7 cells. Treatment with imatinib increases the expression of osteoprotegerin in bone marrow from patients with CML and osteoblastic cells.<\/jats:p>\n               <jats:p>Conclusions: Taken together with recent in vivo data, these results suggest a role for the molecular targets of imatinib in bone cell function, that inhibition by imatinib of PDGFR signaling in osteoblasts activates bone formation, and that the antiresorptive actions of imatinib are mediated by both stromal cell-dependent and direct effects on osteoclast precursors.<\/jats:p>","DOI":"10.1359\/jbmr.070719","type":"journal-article","created":{"date-parts":[[2007,7,30]],"date-time":"2007-07-30T18:51:06Z","timestamp":1185821466000},"page":"1679-1689","source":"Crossref","is-referenced-by-count":118,"title":["Imatinib Promotes Osteoblast Differentiation by Inhibiting PDGFR Signaling and Inhibits Osteoclastogenesis by Both Direct and Stromal Cell-Dependent Mechanisms"],"prefix":"10.1093","volume":"22","author":[{"given":"Susannah","family":"O'Sullivan","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorit","family":"Naot","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Callon","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran","family":"Porteous","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Horne","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Wattie","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen","family":"Watson","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Cornish","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Browett","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Grey","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024020319254083800_bib1","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1056\/NEJMra013339","article-title":"Imatinib mesylate-a new oral targeted therapy","volume":"346","author":"Savage","year":"2002","journal-title":"N Engl J Med"},{"key":"2024020319254083800_bib2","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.1182\/blood-2004-10-3967","article-title":"Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib","volume":"105","author":"Dewar","year":"2005","journal-title":"Blood"},{"key":"2024020319254083800_bib3","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/sj.onc.1209007","article-title":"FMS receptor for M-CSF (CSF-1) is sensitive to the kinase inhibitor imatinib and mutation of Asp-802 to Val confers resistance","volume":"25","author":"Taylor","year":"2006","journal-title":"Oncogene"},{"key":"2024020319254083800_bib4","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1056\/NEJMoa022457","article-title":"Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia","volume":"348","author":"O'Brien","year":"2003","journal-title":"N Engl J Med"},{"key":"2024020319254083800_bib5","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1016\/S0959-8049(02)00836-5","article-title":"Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. 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