title: The orally available Btk inhibitor ibrutinib (PCI-32765) protects against osteoclast-mediated bone loss.
abstract: Bone-resorbing osteoclasts play an essential role in normal bone homeostasis, as well as in various bone disorders such as osteoporosis and rheumatoid arthritis. Previously we showed that the Tec family of tyrosine kinases is essential for the differentiation of osteoclasts and the inhibition of Btk is a promising strategy for the prevention of the bone loss in osteoclast-associated bone disorders. Here we demonstrate that an orally available Btk inhibitor, ibrutinib (PCI-32765), suppresses osteoclastic bone resorption by inhibiting both osteoclast differentiation and function. Ibrutinib downregulated the expression of NFATc1, the key transcription factor for osteoclastogenesis, and disrupted the formation of the actin ring in mature osteoclasts. In addition, genome-wide screening revealed that Btk regulates the expression of the genes involved in osteoclast differentiation and function in both an NFATc1-dependent and -independent manner. Finally, we showed that ibrutinib administration ameliorated the bone loss that developed in a RANKL-induced osteoporosis mouse model. Thus, this study suggests ibrutinib to be a promising therapeutic agent for osteoclast-associated bone diseases.
authors: Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan; Department of Systems BioMedicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Masahiro
authors: M
authors: Shinohara
authors: Pharmacyclics, Inc., Research Department, Sunnyvale, CA 94085-4521, USA.
authors: Betty Y
authors: BY
authors: Chang
authors: Pharmacyclics, Inc., Research Department, Sunnyvale, CA 94085-4521, USA.
authors: Joseph J
authors: JJ
authors: Buggy
authors: Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan; Department of Immunology, Graduate School of Medicine, The University of Tokyo, Japan; Japan Science and Technology Agency (JST), Explorative Research for Advanced Technology (ERATO) Program, Takayanagi Osteonetwork Project, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Yusuke
authors: Y
authors: Nagai
authors: Department of Molecular Biology and Medicine, Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan.
authors: Tatsuhiko
authors: T
authors: Kodama
authors: Department of Systems BioMedicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Hiroshi
authors: H
authors: Asahara
authors: Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan; Department of Immunology, Graduate School of Medicine, The University of Tokyo, Japan; Japan Science and Technology Agency (JST), Explorative Research for Advanced Technology (ERATO) Program, Takayanagi Osteonetwork Project, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: takayana@m.u-tokyo.ac.jp.
authors: Hiroshi
authors: H
authors: Takayanagi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000284:Administration, Oral; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001862:Bone Resorption / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010024:Osteoporosis / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D053245:RANK Ligand
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D053245:RANK Ligand; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000225:Adenine
keywords: Btk; Ibrutinib; Inflammatory bone destruction; Osteoclast; Osteoporosis