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.
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Acknowledgements
We thank Dr. Shigeaki Kato (University of Tokyo) and Dr. Xu Jiake (West Australia University) for CTSK-Cre mice. This research was supported by Grant Nos. 31701033, 31600964, U1301222, 81625015, 81530070, 31529002 from the National Natural Sciences Foundation of China, 2016A030310400 from Natural Science Foundation of Guangdong Province of China, 2015CB55360 from the State Key Development Program for Basic Research of China.
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Song Xu, Yue Zhang, and Jian Wang contributed equally to this work.
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Xu, S., Zhang, Y., Wang, J. et al. TSC1 regulates osteoclast podosome organization and bone resorption through mTORC1 and Rac1/Cdc42. Cell Death Differ 25, 1549–1566 (2018). https://doi.org/10.1038/s41418-017-0049-4
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DOI: https://doi.org/10.1038/s41418-017-0049-4
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