Pathophysiology of scoliosis caused by melatonin deficiency: functional analysis with a candidate causative gene, Tbx1

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K09303
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Kagoshima University
• Principal Investigator: Kawamura Ichiro 鹿児島大学, 医歯学域鹿児島大学病院, 助教 (90535832)
• Co-Investigator(Kenkyū-buntansha): 前田 真吾 鹿児島大学, 医歯学総合研究科, 特任教授 (60353463) ; 谷口 昇 鹿児島大学, 医歯学域医学系, 教授 (20626866)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 側弯症 / 神経筋原性 / メラトニン

Outline of Final Research Achievements

To investigate the mechanisms leading to scoliosis downstream of the melatonin pathway, we investigated the Tbx1 gene in vitro by genome-wide association analysis (GWAS), but its effects on bone, cartilage, and muscle differentiation were weak. Therefore, we focused on the analysis of SCO-spondin (Sspo) and UTS2R, which are associated with the pineal gland; experiments using Urotensin, UTS2R inhibitors, and siRNA confirmed that UTS2R is involved in muscle differentiation. Furthermore, to confirm the in vivo phenotype of UTS2R, UTS2R knockout mice were generated, but no obvious phenotypic differences in the musculoskeletal system were observed, and UTS2R alone could not explain the mechanism of spinal deformity. Combined involvement with other pathways was suggested.

Free Research Field

脊椎

Academic Significance and Societal Importance of the Research Achievements

思春期特発性側弯症は小児の約2％に発症し、その原因や機序は未解明であるが、左右の傍脊柱筋も原因の1つと言われている。ゲノムワイド関連解析で指摘されたTbx1遺伝子や、動物モデルで側弯症が発生することが確認されたSspo、さらにその下流で筋に発現するUTS2Rとの関係を解析した。UTS2Rが筋細胞の分化と関連することはわかったが、動物モデル解析ではUTS2R単独で側弯症を引き起こす要因にはなりえなかった。しかしながら、これらを解明することにより、特に脊柱左右の筋制御に関与する分子メカニズム異常による側弯症の発生病態を明らかにし、新たな治療選択や進行予測に繋がる可能性が考えられる。