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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\n            <jats:italic>DMP1<\/jats:italic>\n            -Cre-directed\n            <jats:italic>Tsc1<\/jats:italic>\n            gene deletion (\n            <jats:italic>Tsc1<\/jats:italic>\n            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\n            <jats:italic>Sost<\/jats:italic>\n            . Our findings reveal a role of TSC1\/mTORC1 signalling in the regulation of osteocyte sclerostin secretion and bone formation in response to mechanical loading\n            <jats:italic>in vitro<\/jats:italic>\n            . Targeting TSC1 represents a potential strategy to increase osteogenesis and prevent bone loss-related diseases.\n          <\/jats:p>","DOI":"10.1098\/rsob.180262","type":"journal-article","created":{"date-parts":[[2019,5,15]],"date-time":"2019-05-15T07:06:27Z","timestamp":1557903987000},"update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Osteocyte TSC1 promotes sclerostin secretion to restrain osteogenesis in mice"],"prefix":"10.1098","volume":"9","author":[{"given":"Wen","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Mental Health of the Ministry of Education, Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key 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