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2019 Fiscal Year Final Research Report

mTORC1 as a therapeutic target for XLH

Research Project

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Project/Area Number 17K10092
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pediatrics
Research InstitutionOsama Woman's and Children's Hospital

Principal Investigator

Masanobu Kawai  地方独立行政法人大阪府立病院機構大阪母子医療センター(研究所), 環境影響部門, 主任研究員 (50598117)

Project Period (FY) 2017-04-01 – 2020-03-31
Keywordsリン / インスリン / PTEN / mTORC1 / FGF23
Outline of Final Research Achievements

Fibroblast growth factor 23 (FGF23) has been centric to the regulation of phosphate (Pi) metabolism; however, the regulatory network of FGF23 in osteocytes has not yet been defined in detail. In addition, accumulating evidence demonstrates the role for insulin signaling in the regulation of Fgf23 in bone. We herein investigated the role of PTEN (phosphatase and tensin homolog deleted from chromosome 10) in this regulation. We created mice lacking Pten expression mainly in osteocytes by crossing Pten-flox mice with Dmp1-Cre mice. The lack of Pten in the osteocytes of these mice was associated with decreased serum Fgf23 levels, which, in turn, resulted in reductions of urinary Pi excretion and elevations of serum Pi levels. Mechanistically, the insulin-induced suppression of Fgf23 expression was reversed in cells treated with the mTORC1 inhibitor, rapamycin.

Free Research Field

小児内分泌、骨代謝

Academic Significance and Societal Importance of the Research Achievements

近年、リン代謝制御機構が明らかとなってきており、インスリンシグナルによるFGF23制御機構が注目されている。臨床的には、インスリン抵抗性をきたすような肥満患者では、FGF23濃度が増加しており、肥満の病態形成におけるFGF23の役割が明らかになってきているが、その分子機序は不明であった。本研究成果は、インスリンによるFGF23制御機構の分子機序を明らかにしたものであり、骨細胞におけるインスリンシグナルが肥満症の病態形成に与える影響を理解する上で、重要な意味があると考えられる。

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Published: 2021-02-19  

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