TY - JOUR
T1 - TSC1 regulates osteoclast podosome organization and bone resorption through mTORC1 and Rac1/Cdc42
AU - Xu, Song
AU - Zhang, Yue
AU - Wang, Jian
AU - Li, Kai
AU - Tan, Kang
AU - Liang, Kangyan
AU - Shen, Junhui
AU - Cai, Daozhang
AU - Jin, Dadi
AU - Li, Mangmang
AU - Xiao, Guozhi
AU - Xu, Jiake
AU - Jiang, Yu
AU - Bai, Xiaochun
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85040773686&partnerID=8YFLogxK
U2 - 10.1038/s41418-017-0049-4
DO - 10.1038/s41418-017-0049-4
M3 - Article
C2 - 29358671
AN - SCOPUS:85040773686
SN - 1350-9047
VL - 25
SP - 1549
EP - 1566
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 9
ER -