Tyrosine Kinases Btk and Tec Regulate Osteoclast Differentiation by Linking RANK and ITAM Signals

Masahiro Shinohara, Takako Koga, Kazuo Okamoto, Shinya Sakaguchi, Kimiko Arai, Hisataka Yasuda, Toshiyuki Takai, Tatsuhiko Kodama, Tomohiro Morio, Raif S. Geha, Daisuke Kitamura, Tomohiro Kurosaki, Wilfried Ellmeier, Hiroshi Takayanagi

Research output: Contribution to journalArticlepeer-review

219 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)794-806
Number of pages13
JournalCell
Volume132
Issue number5
DOIs
Publication statusPublished - 2008 Mar 7

Keywords

  • HUMDISEASE
  • MOLIMMUNO
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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