Elucidation of regulatory mechanisms of skeletal via Smad4

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K11026
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Saitama Medical University
• Principal Investigator: Tsukamoto Sho 埼玉医科大学, 医学部, 助教 (20707658)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 骨形成 / 骨系統疾患 / 骨粗鬆症 / シグナル伝達

Outline of Final Research Achievements

Members of the transforming growth factor-β (TGF-β) family regulate skeletal formation through activating Smad transcription factors. Smad4 is a critical coactivator essential for the Smad-dependent intracellular signaling. We established Smad4 conditional knockout (Smad4 cKO) mice under the control of tamoxifen. The Smad4 cKO mice showed an increase in bone mass in trabecular bone. They also showed an increase in β-catenin positive osteoblasts in spongiosa. The analysis of the Wnt signaling related genes revealed that expression of Wnt7b was increased in Smad4 cKO mice. These results suggest that the inhibition of Smad4-dependent signaling enhances bone formation through increased expression of Wnt7b.

Free Research Field

病態生理学

Academic Significance and Societal Importance of the Research Achievements

本研究から、出生後におけるSmad4を介したシグナルは、骨形成を抑制している可能性を見出した。さらに、TGF-βファミリーと骨形成を強力に亢進するWntシグナルの新たなクロストークの発見は、骨粗鬆症をはじめとした骨代謝関連の疾患の新たな治療標的となる可能性がある。