@article{fd57d6a58f324e0780303358fc6f30f2,
title = "Tyrosine Kinases Btk and Tec Regulate Osteoclast Differentiation by Linking RANK and ITAM Signals",
abstract = "Certain autoimmune diseases result in abnormal bone homeostasis, but association of immunodeficiency with bone is poorly understood. Osteoclasts, which derive from bone marrow cells, are under the control of the immune system. Differentiation of osteoclasts is mainly regulated by signaling pathways activated by RANK and immune receptors linked to ITAM-harboring adaptors. However, it is unclear how the two signals merge to cooperate in osteoclast differentiation. Here we report that mice lacking the tyrosine kinases Btk and Tec show severe osteopetrosis caused by a defect in bone resorption. RANK and ITAM signaling results in formation of a Btk(Tec)/BLNK(SLP-76)-containing complex and PLCγ-mediated activation of an essential calcium signal. Furthermore, Tec kinase inhibition reduces osteoclastic bone resorption in models of osteoporosis and inflammation-induced bone destruction. Thus, this study reveals the importance of the osteoclastogenic signaling complex composed of tyrosine kinases, which may provide the molecular basis for a new therapeutic strategy.",
keywords = "HUMDISEASE, MOLIMMUNO, SIGNALING",
author = "Masahiro Shinohara and Takako Koga and Kazuo Okamoto and Shinya Sakaguchi and Kimiko Arai and Hisataka Yasuda and Toshiyuki Takai and Tatsuhiko Kodama and Tomohiro Morio and Geha, {Raif S.} and Daisuke Kitamura and Tomohiro Kurosaki and Wilfried Ellmeier and Hiroshi Takayanagi",
note = "Funding Information: We thank T. Kitamura, H. Mano, K. Mori, Y. Tomimori, H. Yanagawa, and E. Miyamoto for reagents and technical advice. We also thank M. Isobe-Ohba, T. Nakashima, M. Asagiri, K. Nishikawa, H.J. Gober, K. Kuroda, S. Ochi, Y. Suzuki, and H. Murayama for helpful discussion and assistance. This work was supported in part by a Grant-in-Aid for Creative Scientific Research from the Japan Society for the Promotion of Science (JSPS); grants for the Genome Network Project from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT); Health Sciences Research grants from the Ministry of Health, Labor, and Welfare of Japan; the Austrian Science Fund and the START Program of the Austrian Ministry of Education, Science, and Culture; and grants from Kanae Foundation for Life and Socio-Medical Science, Tokyo Biochemical Research Foundation, Yokoyama Foundation for Clinical Pharmacology, and Hayashi Memorial Foundation for Female Natural Scientists. No authors have any financial interest related to this work. ",
year = "2008",
month = mar,
day = "7",
doi = "10.1016/j.cell.2007.12.037",
language = "English",
volume = "132",
pages = "794--806",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}