TSC1 regulates osteoclast podosome organization and bone resorption through mTORC1 and Rac1/Cdc42

Song Xu, Yue Zhang, Jian Wang, Kai Li, Kang Tan, Kangyan Liang, Junhui Shen, Daozhang Cai, Dadi Jin, Mangmang Li, Guozhi Xiao, Jiake Xu, Yu Jiang, Xiaochun Bai

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1549–1566
JournalCell Death and Differentiation
Volume25
Issue number9
DOIs
Publication statusPublished - Sep 2018

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    Xu, S., Zhang, Y., Wang, J., Li, K., Tan, K., Liang, K., Shen, J., Cai, D., Jin, D., Li, M., Xiao, G., Xu, J., Jiang, Y., & Bai, X. (2018). TSC1 regulates osteoclast podosome organization and bone resorption through mTORC1 and Rac1/Cdc42. Cell Death and Differentiation, 25(9), 1549–1566. https://doi.org/10.1038/s41418-017-0049-4