Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals.
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 PLCgamma-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.
Shinohara
Masahiro
M
Department of Cell Signaling, Graduate School, Tohoku University, Seiryo-machi 4-1, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
Koga
Takako
T
Okamoto
Kazuo
K
Sakaguchi
Shinya
S
Arai
Kimiko
K
Yasuda
Hisataka
H
Takai
Toshiyuki
T
Kodama
Tatsuhiko
T
Morio
Tomohiro
T
Geha
Raif S
RS
Kitamura
Daisuke
D
Kurosaki
Tomohiro
T
Ellmeier
Wilfried
W
Takayanagi
Hiroshi
H
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000077329:Agammaglobulinaemia Tyrosine Kinase; D020816:Amino Acid Motifs; D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D020013:Calcium Signaling; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010022:Osteopetrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010024:Osteoporosis / Q000378:metabolism / Q000473:pathology; D051966:Phospholipase C gamma / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D010750:Phosphoproteins; D053245:RANK Ligand; C092947:SLP-76 signal Transducing adaptor proteins; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D051966:Phospholipase C gamma