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