Open AccessOsteocyte TSC1 promotes sclerostin secretion to restrain osteogenesis in mice
Author(s) -
Wen Liu,
Zhenyu Wang,
Jun Yang,
Yongkui Wang,
Kai Li,
Bin Huang,
Bo Yan,
Ting Wang,
Mangmang Li,
Zhipeng Zou,
Jian Yang,
Guozhi Xiao,
ZhongKai Cui,
Anling Liu,
Xiaochun Bai
Publication year - 2019
Publication title -
open biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.078
H-Index - 53
ISSN - 2046-2441
DOI - 10.1098/rsob.180262
Subject(s) - sclerostin , osteocyte , mtorc1 , dmp1 , downregulation and upregulation , microbiology and biotechnology , endocrinology , medicine , tsc1 , osteoblast , biology , chemistry , pi3k/akt/mtor pathway , wnt signaling pathway , immunology , signal transduction , in vitro , biochemistry , gene , virus , viral matrix protein
Osteocytes secrete the glycoprotein sclerostin to inhibit bone formation by osteoblasts, but how sclerostin production is regulated in osteocytes remains unclear. Here, we show that tuberous sclerosis complex 1 (TSC1) in osteocytes promotes sclerostin secretion through inhibition of mechanistic target of rapamycin complex 1 (mTORC1) and downregulation of Sirt1. We generated mice with DMP1 -Cre-directed Tsc1 gene deletion ( Tsc1 CKO) to constitutively activate mTORC1 in osteocytes. Although osteocyte TSC1 disruption increased RANKL expression and osteoclast formation, it markedly reduced sclerostin production in bone, resulting in severe osteosclerosis with enhanced bone formation in mice. Knockdown of TSC1 activated mTORC1 and decreased sclerostin, while rapamycin inhibited mTORC1 and increased sclerostin mRNA and protein expression levels in MLO-Y4 osteocyte-like cells. Furthermore, mechanical loading activated mTORC1 and prevented sclerostin expression in osteocytes. Mechanistically, TSC1 promotes sclerostin production and prevents osteogenesis through inhibition of mTORC1 and downregulation of Sirt1, a repressor of the sclerostin gene Sost . Our findings reveal a role of TSC1/mTORC1 signalling in the regulation of osteocyte sclerostin secretion and bone formation in response to mechanical loading in vitro . Targeting TSC1 represents a potential strategy to increase osteogenesis and prevent bone loss-related diseases.