Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals
Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals
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DOI：
10.1016/j.cell.2007.12.037
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发表时间：
2008-03-07
期刊：
影响因子：
64.5
通讯作者：
Takayanagi, Hiroshi
中科院分区：
文献类型：
--
作者：
Shinohara, Masahiro;Koga, Takako;Takayanagi, Hiroshi
某些自身免疫性疾病导致骨稳态异常，但免疫缺陷与骨的关系知之甚少。破骨细胞来源于骨髓细胞，受免疫系统控制。破骨细胞的分化主要由RANK和与ITAM-携带衔接子连接的免疫受体激活的信号通路调节。然而，目前还不清楚这两种信号如何合并，以合作破骨细胞分化。在这里，我们报告说，小鼠缺乏酪氨酸激酶Btk和Tec表现出严重的骨石症引起的骨吸收缺陷。RANK和ITAM信号传导导致形成含Btk（Tec）/BLNK（SLP-76）的复合物和PLC γ介导的必需钙信号激活。此外，Tec激酶抑制减少骨质疏松症和炎症诱导的骨破坏模型中的骨吸收。因此，本研究揭示了由酪氨酸激酶组成的破骨细胞生成信号复合物的重要性，这可能为新的治疗策略提供分子基础。
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 PLC gamma-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.