Elucidation of disease mechanism and therapy of FGFR3 skeletal dysplasia using patient-derived iPSCs

• Project/Area Number: 26861716
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Surgical dentistry
• Research Institution: Kyoto University
• Principal Investigator: Yamashita Akihiro 京都大学, iPS細胞研究所, 特定拠点助教 (00636855)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: iPS細胞 / 軟骨 / 骨系統疾患 / FGFR3 / 創薬

Outline of Final Research Achievements

Gain-of-function mutations in the fibroblast growth factor receptor 3 gene (FGFR3) result in skeletal dysplasias, such as thanatophoric dysplasia (TD) and achondroplasia (ACH). The lack of disease models using human cells has hampered the identification of a clinically effective treatment for these diseases. Here, we have generated induced pluripotent stem cells (iPSCs) from patients’ fibroblasts to establish iPSC disease models, followed by their differentiation toward chondrocytes. The chondrogenic differentiation of patients-iPSCs resulted in the formation of degraded cartilage. We found that statins could rescue the degraded cartilage in both chondrogenically differentiated patients-iPSCs. Treatment of ACH model mice with the statin led to a significant recovery of bone growth. These results suggest that statins could represent a medical treatment for infants and children with FGFR3 skeletal dysplasia.

Research Products

• [Journal Article] Limited immunogenicity of human iPS cell-derived cartilage (2016)
  • Author(s): Kimura T, Yamashita A, Ozono K, Tsumaki N
  • Journal Title: Tissue Eng Part A Volume: 22 Pages: 1367-1367
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pterosin B prevents chondrocyte hypertrophy and osteoarthritis in mice by inhibiting Sik3. (2016)
  • Author(s): Yahara Y, Takemori H, Okada M, Kosai A, Yamashita A, Kobayashi T, Fujita K, Itoh Y, Nakamura M, Fuchino H, Kawahara N, Fukui N, Watanabe A, Kimura T, Tsumaki N.
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 10959-10959
  • DOI: 10.1038/ncomms10959
  • NAID: 120005741112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] iPS細胞を用いた軟骨疾患に対する再生医療開発 (2016)
  • Author(s): 山下晃弘、妻木範行
  • Journal Title: 月刊糖尿病 Volume: 8 Pages: 91-91
• [Journal Article] Generation of Scaffoldless Hyaline Cartilaginous Tissue from Human iPSCs (2015)
  • Author(s): Yamashita, A., Morioka, M., Yahara, Y., Okada, M., Kobayashi, T., Kuriyama, S., Matsuda, S., and Tsumaki, N
  • Journal Title: Stem cell reports Volume: 4 Issue: 3 Pages: 404-418
  • DOI: 10.1016/j.stemcr.2015.01.016
  • NAID: 120005767006
  • Peer Reviewed / Open Access
• [Journal Article] Modeling type II collagenopathy skeletal dysplasia by directed conversion and induced pluripotent stem cells (2015)
  • Author(s): Okada M, Ikegawa S, Morioka M, Yamashita A, Saito A, Sawai H,Murotsuki J, Ohashi H, Okamoto T, Nishimura G, Imaizumi K, Tsumaki N
  • Journal Title: Hum Mol Genet Volume: 24 Issue: 2 Pages: 299-313
  • DOI: 10.1093/hmg/ddu444
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] iPS cell technologies and cartilage regeneration (2015)
  • Author(s): Tsumaki N, Okada M, Yamashita A
  • Journal Title: Bone Volume: 70 Pages: 48-54
  • DOI: 10.1016/j.bone.2014.07.011
  • Peer Reviewed
• [Journal Article] Statin treatment rescues FGFR3 skeletal dysplasia phenotypes (2014)
  • Author(s): Yamashita A, Morioka M, Kishi H, Kimura T, Yahara Y, Okada M, Fujita,K, Sawai H, Ikegawa S, Tsumaki N.
  • Journal Title: Nature Volume: 513(7519) Issue: 7519 Pages: 507-11
  • DOI: 10.1038/nature13775
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] フィーダーフリーiPS細胞から移植用軟骨の作成 (2017)
  • Author(s): 山下晃弘, 森岡美帆、小林与人、奥谷祐希、栗山新一、小屋松冴子、矢島伸之、島伸行、松田秀一、妻木範行
  • Organizer: 軟骨代謝学会
  • Place of Presentation: 京都
  • Year and Date: 2017-03-03
• [Presentation] Regenerative treatment of focal defects of articular cartilage with iPS cell-derived cartilage (2016)
  • Author(s): Yamashita A, Tsumaki N
  • Organizer: APLAR
  • Place of Presentation: 上海
  • Year and Date: 2016-09-27
  • Int'l Joint Research / Invited
• [Presentation] ヒトiPS細胞由来軟骨の開発 (2016)
  • Author(s): 山下 晃弘, 妻木 範行
  • Organizer: 骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 2016-07-21
  • Invited
• [Presentation] ヒトiPS細胞由来軟骨を用いた関節軟骨再生治療の試み (2016)
  • Author(s): 山下 晃弘, 妻木 範行
  • Organizer: 日本炎症・再生医学会
  • Place of Presentation: 京都
  • Year and Date: 2016-06-16
  • Invited
• [Presentation] スタチンによるFGFR3軟骨形成異常症の病態回復 (2016)
  • Author(s): 山下 晃弘、森岡 美帆、岸 宏美、木村 武司、箭原 康人、岡田 稔、藤田 香里、澤井 英明、池川 志郎、妻木範行
  • Organizer: 軟骨代謝学会
  • Place of Presentation: 広島
  • Year and Date: 2016-02-19
  • Invited
• [Presentation] iPS細胞技術を用いた軟骨疾患治療方法の開発 (2016)
  • Author(s): 山下 晃弘
  • Organizer: 立命館大学 細胞工学特論
  • Place of Presentation: 滋賀
  • Year and Date: 2016-01-13
  • Invited
• [Presentation] スタチンによるFGFR3軟骨形成異常症の病態回復 – iPS細胞疾患モデルを用いて– (2015)
  • Author(s): 山下 晃弘、妻木 範行。
  • Organizer: 第30回日本整形外科学会基礎学術集会
  • Place of Presentation: 富山
  • Year and Date: 2015-10-22
  • Invited
• [Presentation] iPS細胞疾患モデルを用いたFGFR3軟骨形成異常症の研究 (2015)
  • Author(s): 山下 晃弘、妻木 範行
  • Organizer: 骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-23
  • Invited
• [Presentation] ヒトiPS細胞を用いた移植可能な軟骨様組織の作成 (2015)
  • Author(s): 山下晃弘, 森岡美帆、箭原康人、岡田稔、妻木範行
  • Organizer: 再生医療学会
  • Place of Presentation: 横浜
  • Year and Date: 2015-03-19 – 2015-03-21
• [Presentation] ヒトiPS細胞から硝子軟骨様組織への分化誘導法の確立 (2015)
  • Author(s): 山下晃弘, 森岡美帆、箭原康人、岡田稔、小田直純、妻木範行
  • Organizer: 軟骨代謝学会
  • Place of Presentation: 東京
  • Year and Date: 2015-03-06 – 2015-03-07
• [Presentation] iPS細胞を使った軟骨疾患治療法の開発 (2015)
  • Author(s): 山下 晃弘
  • Organizer: 第３回労災医療研修会
  • Place of Presentation: 大阪府医師会館
  • Year and Date: 2015-02-20
  • Invited
• [Presentation] Statin treatment rescues FGFR3 skeletal dysplasia phenotypes (2015)
  • Author(s): Yamashita A, Morioka M, Kishi H, Kimura T, Yahara Y, Okada M, Fujita K, Sawai H, Ikegawa S, Tsumaki N.
  • Organizer: Takeda symposium
  • Place of Presentation: Osaka
  • Year and Date: 2015-01-15 – 2015-01-17
• [Presentation] スタチンによるFGFR3病の病態改善 ー疾患特異的iPS細胞を用いてー (2014)
  • Author(s): 山下 晃弘
  • Organizer: 第17回日本骨代謝研究会
  • Place of Presentation: 慶応義塾大学
  • Year and Date: 2014-11-27
  • Invited
• [Presentation] ヒトiPS細胞から軟骨細胞への分化誘導 (2014)
  • Author(s): 山下 晃弘, 妻木 範行
  • Organizer: 日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-07-24 – 2014-07-26
  • Invited
• [Remarks] ヒトiPS細胞から硝子軟骨の作製～関節軟骨損傷の再生治療法開発へ向けて～
  • URL: https://www.cira.kyoto-u.ac.jp/j/pressrelease/news/150227-105807.html
• [Remarks] スタチンが軟骨無形成症の病態を回復
  • URL: http://www.cira.kyoto-u.ac.jp/j/research/finding/140918-084300.html