Elucidation of the transcriptional regulation of Runx2 and development of the drugs for osteoporosis and osteoarthritis

2018 Fiscal Year Final Research Report

• Project/Area Number: 26221310
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Morphological basic dentistry
• Research Institution: Nagasaki University
• Principal Investigator: KOMORI Toshihisa 長崎大学, 医歯薬学総合研究科(歯学系), 教授 (00252677)
• Co-Investigator(Kenkyū-buntansha): 川根 徹也 長崎大学, 医歯薬学総合研究科(歯学系), 技術職員 (00265208) ; 宮崎 敏博 長崎大学, 医歯薬学総合研究科(歯学系), 准教授 (10174161) ; 森石 武史 長崎大学, 医歯薬学総合研究科(歯学系), 助教 (20380983) ; 増山 律子 長崎大学, 医歯薬学総合研究科(歯学系), 准教授 (60297596)
• Project Period (FY): 2014-05-30 – 2019-03-31
• Keywords: 骨芽細胞 / 軟骨細胞 / エンハンサー / Runx2

Outline of Final Research Achievements

The transcription of Runx2 is regulated by enhancers. We identified three chondrocyte-specific enhancers of Runx2. We recapitulated the physiological Runx2 expression in osteoblasts and chondrocytes using the three enhancers and 343 bp osteoblast-specific enhancer. However, the deletion of each of the four regions showed no phenotype in mice. Therefore, we selected other 19 candidate regions for enhancers, and generated their deleted mice. So far, we could not find prominent phenotypes in these mice. Thus, it is considered that the transcription of Runx2 is regulated by multiple enhancers, which have redundant functions. We identified a chemical compound by high throughput screening using 343 bp osteoblast-specific enhancer. The chemical compound enhanced the enhancer activity, Runx2 mRNA, and osteoblast differentiation in vitro, and increased bone volume and bone density in mice.

Free Research Field

生物系、医歯薬学、歯学

Academic Significance and Societal Importance of the Research Achievements

細胞系列特異的発現が機能重複した多数のエンハンサー群によって制御されていることを示した。これは、転写制御研究に大きな意義を持つ。さらに骨芽細胞特異的エンハンサーを用いてマウスで骨量を増加させる化合物を同定出来た。これは、骨形成を促進させる骨粗鬆症治療薬の開発に繋がる成果である。また、軟骨細胞特異的エンハンサーの同定により、変形性関節症の治療薬の開発が可能になった。