title: Tyrosine Kinase Inhibitors Regulate OPG through Inhibition of PDGFRβ.
abstract: Nilotinib and imatinib are tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). In vitro, imatinib and nilotinib inhibit osteoclastogenesis, and in patients they reduce levels of bone resorption. One of the mechanisms that might underlie these effects is an increase in the production of osteoprotegerin (OPG). In the current work we report that platelet-derived growth factor receptor beta (PDGFRβ) signaling regulates OPG production in vitro. In addition, we have shown that TKIs have effects on RANKL signaling through inhibition of the PDGFRβ and other target receptors. These findings have implications for our understanding of the mechanisms by which TKIs affect osteoclastogenesis, and the role of PDGFRβ signaling in regulating osteoclastogenesis. Further studies are indicated to confirm the clinical effects of PDGFRβ-inhibitors and to elaborate the intracellular pathways that underpin these effects.
authors.affiliation: Department of Pharmacology, University of Auckland, Auckland, New Zealand.
authors.forename: Susannah
authors.identifier: http://orcid.org/0000-0002-1792-8580
authors.initials: S
authors.lastname: O'Sullivan
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Mei Lin
authors.initials: ML
authors.lastname: Tay
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Lin
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Usha
authors.initials: U
authors.lastname: Bava
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Karen
authors.initials: K
authors.lastname: Callon
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Jillian
authors.initials: J
authors.lastname: Cornish
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Dorit
authors.initials: D
authors.lastname: Naot
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Andrew
authors.initials: A
authors.lastname: Grey
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D000068877:Imatinib Mesylate / Q000633:toxicity*; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D053245:RANK Ligand / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D053244:Osteoprotegerin; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D053245:RANK Ligand; D034741:RNA, Small Interfering; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta