Development of new therapy for osteogenesis imperfecta targeting bone coupling

• Project/Area Number: 18K15708
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Osaka University
• Principal Investigator: Ohata Yasuhisa 大阪大学, 大学院医学系研究科, 助教 (20805460)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 骨形成不全症 / 破骨細胞 / 骨芽細胞 / 骨カップリング / 骨リモデリング

Outline of Final Research Achievements

Osteogenesis imperfecta (OI) is a congenital bone dysplasia with bone fragility. Previous sudies have suggested that abnormalities in bone coupling accelerated bone resorption by osteoclasts, which exacerbate the OI pathology. The aim of this study was to develop a novel treatment for OI targeting bone coupling abnormalities. We extracted bone marrow from oim mice, an OI model mouse, and performed primary osteoblast culture. Then we comprehensively identified molecules involved in osteoclast differentiation using RNAseq. In this study, we established an experimental system for analyzing bone evaluation in OI model mice and a method for isolating osteoblasts and osteoclasts, and confirmed that osteoclast differentiation is actually enhanced in OI. Finally, we identified candidate molecules that could be responsible for enhanced osteoclast differentiation.

Academic Significance and Societal Importance of the Research Achievements

本研究では骨形成不全症における破骨細胞機能亢進を惹起する候補分子の同定を行った。さらに候補分子を発現する細胞の特徴をシングルセルRNAseqで解析した。これまで骨形成不全症では病態特異的治療法がなく、特に重症患者においては既存の姑息的治療では、十分な効果が乏しく、QOLの改善につながっていないことが問題となっていた。本研究で見いだされた病態をさらに解明し、候補分子発現細胞を標的とした治療法を検討することにより、より骨形成不全症の病態に特異的な治療法の開発が進められることが期待される。

Research Products

• [Journal Article] A novel <i>COL1A1</i> deletion/insertion pathogenic variant in a patient with osteogenesis imperfecta (2022)
  • Author(s): Yamada Chieko、Kubota Takuo、Ishimi Takeshi、Takeyari Shinji、Yamamoto Kenichi、Nakayama Hirofumi、Ohata Yasuhisa、Fujiwara Makoto、Kitaoka Taichi、Ozono Keiichi
  • Journal Title: Clinical Pediatric Endocrinology Volume: 31 Issue: 3 Pages: 205-208
  • DOI: 10.1297/cpe.2022-0027
  • ISSN: 0918-5739, 1347-7358
• [Journal Article] Genotype-phenotype analysis, and assessment of the importance of the zinc-binding site in PHEX in Japanese patients with X-linked hypophosphatemic rickets using 3D structure modeling (2021)
  • Author(s): Ishihara Y, Ohata Y, Takeyari S, Kitaoka T, Fujiwara M, Nakano Y, Yamamoto K, Yamada C, Yamamoto K, Michigami T, Mabe H, Yamaguchi T, Matsui K, Tamada I, Namba N, Yamamoto A, Etoh J, Kawaguchi A, Kosugi R, Ozono K, Kubota T
  • Journal Title: Bone Volume: 153 Pages: 116135-116135
  • DOI: 10.1016/j.bone.2021.116135
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A case of HDR syndrome coexisting with tetralogy of Fallot, with a novel GATA3 mutation, which manifested as a renal abscess (2021)
  • Author(s): Ikeuchi Mayo、Kiyota Kyoko、Itonaga Tomoyo、Kawano-Matsuda Fumika、Ohata Yasuhisa、Fujiwara Makoto、Kubota Takuo、Ozono Keiichi、Ihara Kenji
  • Journal Title: CEN Case Reports Volume: 10 Issue: 2 Pages: 241-243
  • DOI: 10.1007/s13730-020-00551-0
  • Peer Reviewed / Open Access
• [Journal Article] Alkaline phosphatase in pediatric patients with genu varum caused by vitamin D-deficient rickets (2021)
  • Author(s): Mukai Masashi、Yamamoto Takehisa、Takeyari Shinji、Ohata Yasuhisa、Kitaoka Taichi、Kubota Takuo、Yamamoto Katsusuke、Kijima Eri、Hasegawa Yasuhiro、Michigami Toshimi、Ozono Keiichi
  • Journal Title: Endocrine Journal Volume: 68 Issue: 7 Pages: 807-815
  • DOI: 10.1507/endocrj.EJ20-0622
  • NAID: 130008068265
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Neonatal cholestasis can be the first symptom of McCune-Albright syndrome: A case report (2021)
  • Author(s): Satomura Yoshinori、Bessho Kazuhiko、Kitaoka Taichi、Takeyari Shinji、Ohata Yasuhisa、Kubota Takuo、Ozono Keiichi
  • Journal Title: World Journal of Clinical Pediatrics Volume: 10 Issue: 2 Pages: 7-14
  • DOI: 10.5409/wjcp.v10.i2.7
  • Peer Reviewed / Open Access
• [Journal Article] 4-Phenylbutyric acid enhances the mineralization of osteogenesis imperfecta iPSC-derived osteoblasts (2021)
  • Author(s): Takeyari Shinji、Kubota Takuo、Ohata Yasuhisa、Fujiwara Makoto、Kitaoka Taichi、Taga Yuki、Mizuno Kazunori、Ozono Keiichi
  • Journal Title: Journal of Biological Chemistry Volume: 296 Pages: 100027-100027
  • DOI: 10.1074/jbc.ra120.014709
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Asfotase Alfa on Muscle Weakness in a Japanese Adult Patient of Hypophosphatasia with Low ALP Levels (2020)
  • Author(s): Yagi T, Aotani D, Imaeda K, Ozono K, Kataoka H, Tanaka T.
  • Journal Title: Internal Medicine Volume: 59 Issue: 6 Pages: 811-815
  • DOI: 10.2169/internalmedicine.3298-19
  • NAID: 130007808736
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-03-15
  • Peer Reviewed / Open Access
• [Journal Article] Increased S1P expression in osteoclasts enhances bone formation in an animal model of Paget's disease (2020)
  • Author(s): Nagata Yuki、Miyagawa Kazuaki、Ohata Yasuhisa、Petrusca Daniela N.、Pagnotti Gabriel M.、Mohammad Khalid S.、Guise Theresa A.、Windle Jolene J.、David Roodman G.、Kurihara Noriyoshi
  • Journal Title: Journal of Cellular Biochemistry Volume: 122 Issue: 3-4 Pages: 335-348
  • DOI: 10.1002/jcb.29861
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phenotypes of a family with XLH with a novel PHEX mutation (2020)
  • Author(s): Yamamoto Akiko、Nakamura Toshiro、Ohata Yasuhisa、Kubota Takuo、Ozono Keiichi
  • Journal Title: Human Genome Variation Volume: 7 Issue: 1 Pages: 8-8
  • DOI: 10.1038/s41439-020-0095-1
  • Peer Reviewed / Open Access
• [Journal Article] Complete oculocerebrorenal phenotype of Lowe syndrome in a female patient with half reduction of inositol polyphosphate 5-phosphatase (2020)
  • Author(s): Yamamoto Katsusuke、Hasegawa Yasuhiro、Ohata Yasuhisa、Satomura Kenichi、Mizoguchi Yoshimi、Shimotsuji Tsunesuke、Yamamoto Takehisa
  • Journal Title: CEN Case Reports Volume: 9 Issue: 2 Pages: 95-100
  • DOI: 10.1007/s13730-019-00434-z
  • Peer Reviewed / Open Access
• [Journal Article] Potential pathological role of single nucleotide polymorphism (c.787T&gt;C) in <i>alkaline phosphatase (ALPL)</i> for the phenotypes of hypophosphatasia (2020)
  • Author(s): Matsuda Nozomi、Takasawa Kei、Ohata Yasuhisa、Takishima Shigeru、Kubota Takuo、Ishihara Yasuki、Fujiwara Makoto、Ogawa Erika、Morio Tomohiro、Kashimada Kenichi、Ozono Keiichi
  • Journal Title: Endocrine Journal Volume: 67 Issue: 12 Pages: 1227-1232
  • DOI: 10.1507/endocrj.EJ20-0203
  • NAID: 130007962226
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Osteoclast-derived IGF1 is required for pagetic lesion formation in vivo (2020)
  • Author(s): Miyagawa Kazuaki、Ohata Yasuhisa、Delgado-Calle Jesus、Teramachi Jumpei、Zhou Hua、Dempster David D.、Subler Mark A.、Windle Jolene J.、Chirgwin John M.、Roodman G. David、Kurihara Noriyoshi
  • Journal Title: JCI Insight Volume: 5 Issue: 6
  • DOI: 10.1172/jci.insight.133113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical Practice Guidelines for Achondroplasia* (2020)
  • Author(s): Kubota Takuo、Adachi Masanori、Kitaoka Taichi、Hasegawa Kosei、Ohata Yasuhisa、Fujiwara Makoto、Michigami Toshimi、Mochizuki Hiroshi、Ozono Keiichi
  • Journal Title: Clinical Pediatric Endocrinology Volume: 29 Issue: 1 Pages: 25-42
  • DOI: 10.1297/cpe.29.25
  • NAID: 130007783623
  • ISSN: 0918-5739, 1347-7358
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Practice Guidelines for Hypophosphatasia* (2020)
  • Author(s): Michigami Toshimi、Ohata Yasuhisa、Fujiwara Makoto、Mochizuki Hiroshi、Adachi Masanori、Kitaoka Taichi、Kubota Takuo、Sawai Hideaki、Namba Noriyuki、Hasegawa Kosei、Fujiwara Ikuma、Ozono Keiichi
  • Journal Title: Clinical Pediatric Endocrinology Volume: 29 Issue: 1 Pages: 9-24
  • DOI: 10.1297/cpe.29.9
  • NAID: 130007783622
  • ISSN: 0918-5739, 1347-7358
  • Peer Reviewed / Open Access
• [Journal Article] Parental somatogonadal COL2A1 mosaicism contributes to intrafamilial recurrence in a family with type 2 collagenopathy (2019)
  • Author(s): Yamamoto Kenichi、Kubota Takuo、Takeyari Shinji、Kitaoka Taichi、Miyata Kei、Nakano Yukako、Nakayama Hirofumi、Ohata Yasuhisa、Yanagi Kumiko、Kaname Tadashi、Okada Yukinori、Ozono Keiichi
  • Journal Title: American Journal of Medical Genetics Part A Volume: 182 Issue: 3 Pages: 454-460
  • DOI: 10.1002/ajmg.a.61422
  • Peer Reviewed
• [Journal Article] IGF2 Mutations (2019)
  • Author(s): Masunaga Yohei、Inoue Takanobu、Yamoto Kaori、Fujisawa Yasuko、Sato Yasuhiro、Kawashima-Sonoyama Yuki、Morisada Naoya、Iijima Kazumoto、Ohata Yasuhisa、Namba Noriyuki、Suzumura Hiroshi、Kuribayashi Ryota、Yamaguchi Yu、Yoshihashi Hiroshi、Fukami Maki、Saitsu Hirotomo、Kagami Masayo、Ogata Tsutomu
  • Journal Title: The Journal of Clinical Endocrinology & Metabolism Volume: 105 Issue: 1 Pages: 116-125
  • DOI: 10.1210/clinem/dgz034
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta (2019)
  • Author(s): Ohata Y., Takeyari S., Nakano Y., Kitaoka T., Nakayama H., Bizaoui V., Yamamoto K., Miyata K., Yamamoto K., Fujiwara M., Kubota T., Michigami T., Yamamoto K., Yamamoto T., Namba N., Ebina K., Yoshikawa H., Ozono K.
  • Journal Title: Osteoporosis International Volume: 30 Issue: 11 Pages: 2333-2342
  • DOI: 10.1007/s00198-019-05076-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 海綿骨スコア(TBS)と骨塩見かけ密度(BMAD)は小児骨形成不全症の骨評価に有用 (2022)
  • Author(s): 大幡泰久 , 北岡太一 , 石見壮史 , 山田知絵子 , 中野由佳子 , 武鑓真司 , 山本賢一 , 中山尋文 , 藤原誠 , 窪田拓生 , 大薗恵一
  • Organizer: 第32回臨床内分泌代謝Update
• [Presentation] Year Book 骨代謝・副甲状腺・骨系統疾患 (2022)
  • Author(s): 大幡泰久
  • Organizer: 第55回日本小児内分泌学会学術集会
  • Invited
• [Presentation] Trabecular Bone Score and Bone Mineral Apparent Density Predict the Severity of Bone Fragility in Children and Adolescents with Osteogenesis Imperfecta. A Cross-sectional Study (2022)
  • Author(s): Y. Ohata, T. Kitaoka, T. Ishimi, C. Yamada, Y. Nakano, K. Yamamoto, S. Takeyari, H. Nakayama, M. Fujiwara, T. Kubota, K. Ozono
  • Organizer: American Society for Bone and Mineral Research Annual Meeting 2022
  • Int'l Joint Research
• [Presentation] Genotype-phenotype analysis and the importance of the zinc binding site of PHEX using 3D structure modeling in Japanese patients with X-linked hypophosphatemic rickets (2021)
  • Author(s): Y. Ohata, Y. Ishihara, S. Takeyari, T. Kitaoka, M. Fujiwara, Y. Nakano, K. Yamamoto, C. Yamada, K. Yamamoto, T. Michigami, H. Mabe, T. Yamaguchi, K. Matsui, I. Tamada, N. Namba, A. Yamamoto, J. Etoh, A. Kawaguchi, R. Kosugi, K. Ozono, and T. Kubota
  • Organizer: American society for bone mineral research annual meeting
  • Int'l Joint Research
• [Presentation] Year Book 1 骨代謝 (2021)
  • Author(s): 大幡泰久
  • Organizer: 日本小児内分泌学会
  • Invited
• [Presentation] Genotype-phenotype analysis, and assessment of the importance of the zinc-binding site in PHEX in Japanese patients with X-linked hypophosphatemic rickets using 3D structure modeling (2021)
  • Author(s): 大幡 泰久、石原 康貴、武鑓 真司、北岡 太一、藤原 誠、中野 由佳子、山本 賢一、 山田 知絵子、山本 勝輔、道上 敏美、間部 裕代、山口 健史、松井 克之、玉田 泉、 難波 範行、山本 晶子、江藤 潤也、河口 亜津彩、小杉 理英子、窪田 拓生、大薗 恵一
  • Organizer: 日本小児内分泌学会
• [Presentation] 副甲状腺機能低下症の診断と治療 (2021)
  • Author(s): 大幡泰久
  • Organizer: 臨床内分泌Update
  • Invited
• [Presentation] 長期管理中のStAR異常による46,XX先天性リポイド副腎過形成症の一例 (2021)
  • Author(s): 大幡泰久、山本賢一、中野由佳子、石見壮史、武鑓真司、山田知絵子、藤原誠、北岡太一、三善陽子、窪田拓生、大薗恵一
  • Organizer: 日本ステロイドホルモン学会
• [Presentation] Pathogenic Variants of GNAS Gene Generating Abnormal Amino Acid Sequences in the β6 Strand / α5 Helix of Gsα in 2 Unrelated Japanese Patients with Pseudohypoparathyroidism 1A / Pseudopseudohypoparathyroidism (2020)
  • Author(s): Yasuhisa Ohata, Haruna Kakimoto, Yasuki Ishihara, Makoto Fujiwara, Shinji Takeyari, Taichi Kitaoka, Hirofumi Nakayama, Yukako Nakano, Kenichi Yamamoto, Chieko Yamada, Takeshi Ishimi, Takuo Kubota, Keiichi Ozono
  • Organizer: American society for bone mineral research annual meeting
• [Presentation] Gsαタンパクのβ6 strand /α5 helix部位に異常なアミノ酸配列が付加されるGNAS遺伝子新規変異は偽性副甲状腺機能低下症/偽性偽性副甲状腺機能低下症の原因となりうる-非血縁2家系症例の検討 (2020)
  • Author(s): 大幡泰久、藤原誠、石原康貴、窪田拓生、北岡太一、中山尋文、武鑓真司、山本賢一、中野由佳子、大薗恵一
  • Organizer: 日本骨代謝学会
• [Presentation] Mutational analysis of the PHEX gene and genotype-phenotype correlation in 37 Japanese patients with X-linked hypophosphatemic rickets (2019)
  • Author(s): Yasuhisa Ohata, Takuo Kubota, Shinji Takeyari, Taichi Kitaoka, Yasuki Ishihara, Hirofumi Nakayama, Yukako Nakano, Kenichi Yamamoto, Kei Miyata, Chieko Yamada, Makoto Fujiwara, Katsusuke Yamamoto, Toshimi Michigami, Hiroyo Mabe, Takeshi Yamaguchi, Katsuyuki Matsui, Izumi Tamada, Noriyuki Namba,Keiichi Ozono et al.
  • Organizer: American society for bone mineral research annual meeting
  • Int'l Joint Research
• [Presentation] 日本人XLH患者37名のPHEX遺伝子解析結果と表現型相関の検討 Mutational analysis of the PHEX gene and genotype-phenotype correlation in 37 Japanese patients with X-linked hypophosphatemic rickets (2019)
  • Author(s): 大幡泰久, 石原康貴, 窪田拓生, 武鑓真司, 北岡太一, 中山尋文, 中野由佳子, 山本賢一, 藤原誠, 道上敏美, 難波範行, 大薗恵一
  • Organizer: 日本骨代謝学会
• [Presentation] 日本人XLH患者38名のPHEX遺伝子解析結果と表現型相関の検討 Mutational analysis of the PHEX gene and genotype-phenotype correlation in 38 Japanese patients with X-linked hypophosphatemic rickets (2019)
  • Author(s): 大幡泰久, 石原康貴, 窪田拓生, 武鑓真司, 北岡太一, 中山尋文, 中野由佳子, 山本賢一, 宮田京, 山田知絵子, 藤原誠, 山本勝輔, 道上敏美, 難波範行, 間部裕代, 山口健史, 松井克之, 玉田泉, 山本晶子, 江藤潤也, 河口亜津彩, 大薗恵一
  • Organizer: 日本小児内分泌学会
• [Presentation] Comprehensive Genetic Analysis by Targeted Next Generation Sequencing and Genotype-Phenotype Correlation of 55 Japanese Patients with Osteogenesis Imperfecta (2018)
  • Author(s): Yasuhisa Ohata, Shinji Takeyari, Taichi Kitaoka, Hirofumi Nakayama, Varoona Bizaoui, Yukako Nakano, Kenichi Yamamoto, Kei Miyata, Keiko Yamamoto, Takuo Kubota, Katsusuke Yamamoto, Toshimi Michigami, Takehisa Yamamoto,and Keiichi Ozono
  • Organizer: American society for bone mineral research annual meeting
  • Int'l Joint Research
• [Presentation] Comprehensive genetic analysis by targeted next generation sequencing and genotype-phenotype correlation of 53 Japanese patients with osteogenesis imperfecta (2018)
  • Author(s): Yasuhisa Ohata, Shinji Takeyari, Yukako Nakano, Kenichi Yamamoto, Hirofumi Nakayama, Taichi Kitaoka, Takuo Kubota, Toshimi Michigami, Takehisa Yamamoto, and Keiichi Ozono
  • Organizer: 日本骨代謝学会
• [Presentation] ターゲットエクソーム解析を用いた日本人骨形成不全患者55名の網羅的遺伝子解析と表現型解析 (2018)
  • Author(s): 大幡泰久、武鑓真司、中野由佳子、山本賢一、宮田京、中山尋文、Varoona Bizaoui、北岡太一、窪田拓生、山本勝輔、道上敏美、山本威久、大薗恵一
  • Organizer: 日本小児内分泌学会
• [Book] 小児内分泌学 改訂第3版 (2022)
  • Author(s): 日本小児内分泌学会
  • Total Pages: 688
  • Publisher: 診断と治療社
  • ISBN: 9784787824721