TSC1 regulates osteoclast podosome organization and bone resorption through mTORC1 and Rac1/Cdc42
TSC1 regulates osteoclast podosome organization and bone resorption through mTORC1 and Rac1/Cdc42
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TSC1 通过 mTORC1 和 Rac1/Cdc42 调节破骨细胞足体组织和骨吸收。
DOI：
10.1038/s41418-017-0049-4
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发表时间：
2018-09-01
影响因子：
12.4
通讯作者：
Bai, Xiaochun
中科院分区：
文献类型：
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作者：
Xu, Song;Zhang, Yue;Bai, Xiaochun
足小体进入封闭区的重组对破骨细胞（ocl）吸收骨至关重要，但其潜在机制尚不清楚。在这里，我们发现结节硬化复合体1 （TSC1）通过雷帕霉素复合体1 （mTORC1）和小gtpase Rac1/Cdc42的机制靶点在OCLs中发挥中心作用，促进足体组织和骨吸收。在破骨细胞形成过程中，TSC1表达增强可下调mTORC1活性。OCLs中TSC1的缺失减少了体外足小体带的形成和体内密封带的形成，导致骨吸收不足和骨质疏松。在机制上，TSC1通过释放mtorc1依赖的Rac1/Cdc42负反馈抑制来促进足体上部结构组装。雷帕霉素和活性Rac1/Cdc42可恢复突变小鼠足小体组织和骨吸收，减轻骨质疏松表型。我们的研究结果揭示了TSC1信号在骨吸收调节中的重要作用。靶向TSC1是一种抑制骨吸收和预防骨质流失相关疾病的新策略。
Reorganization of the podosome into the sealing zone is crucial for osteoclasts (OCLs) to resorb bone, but the underlying mechanisms are unclear. Here, we show that tuberous sclerosis complex 1 (TSC1) functions centrally in OCLs to promote podosome organization and bone resorption through mechanistic target of rapamycin complex 1 (mTORC1) and the small GTPases Rac1/Cdc42. During osteoclastogenesis, enhanced expression of TSC1 downregulates mTORC1 activity. TSC1 deletion in OCLs reduced podosome belt formation in vitro and sealing zone formation in vivo, leading to bone resorption deficiency and osteopetrosis. Mechanistically, TSC1 promoted podosome superstructure assembly by releasing mTORC1-dependent negative feedback inhibition of Rac1/Cdc42. Rapamycin and active Rac1/Cdc42 restore podosome organization and bone resorption and alleviate osteopetrotic phenotypes in mutant mice. Our findings reveal an essential role of TSC1 signaling in the regulation of bone resorption. Targeting TSC1 represents a novel strategy to inhibit bone resorption and prevent bone loss-related diseases.