Analysis of mechanism of bone fragility and effects of drugs in osteogenesis imperfecta using a graft model for enchondral bone formation

2021 Fiscal Year Final Research Report

• Project/Area Number: 18H02780
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Osaka University
• Principal Investigator: Ozono Keiichi 大阪大学, 医学系研究科, 教授 (20270770)
• Co-Investigator(Kenkyū-buntansha): 道上 敏美 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), 骨発育疾患研究部門, 部長 (00301804) ; 妻木 範行 京都大学, iPS細胞研究所, 教授 (50303938)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 骨形成不全症 / 骨脆弱性 / 疾患特異的iPS細胞

Outline of Final Research Achievements

We obtained fibroblasts and iPS cells from patients with osteogenesis imperfecta (OI). Collagen type 1 from fibroblasts and osteoblasts differentiated from iPS cells were analyzed by SDS-PAGE and LC/MS. The glycosylation-overmodification of collagen type 1 was found. 4-phenyl butyric acid improved overmodificatin and accumulation of collagen in ER. TGF-b signaling was slightly different between osteoblasts induced from normal and OI patients derived iPS cells. The concentration of sclerostin was related to height and weight in 19 OI patients. Variants responsible for OI was found in 36 out of 47 OI patients. The significant genotype-phenotype correlation was reported. The model mice having p.G810S were generated by the knock-in method and proved to show fragile bone phenotypes.

Free Research Field

骨代謝学

Academic Significance and Societal Importance of the Research Achievements

まだ、有効な治療法のない重症骨形成不全症の治療薬として、ブフェニールを見出した。独自の骨形成不全症モデルマウスを作成し、ブフェニールの効果を判定できる段階となっている。ブフェニールは、他の疾患に適応が取れており、いわゆるdrug repositioningにより、薬剤開発の面でも有利であると考えられる。