Local phosphorus production system in bone mineralization: role of alkaline phosphatase

• Project/Area Number: 17K10076
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Osaka University
• Principal Investigator: Kubota Takuo 大阪大学, 医学系研究科, 講師 (40629135)
• 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), 環境影響部門, 部長 (00301804)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 小児科学、小児骨代謝学 / 小児内分泌学 小児骨代謝学 / 小児内分泌学 / 小児骨代謝学 / 小児科学

Outline of Final Research Achievements

Local phosphorus production system and role of alkaline phosphatase in bone and cartilage mineralization remain to be elucidated. Osteoblast-mediated mineralization study using human bone marrow derived mesenchymal stem cells and induced pluripotent stem cells derived from patients with hypophosphatasia suggested that alkaline phosphatase activity, phosphorus levels, pyrophosphate levels and phosphorus/pyrophosphate ratio affect bone mineralization and osteoblastic differentiation markers.

Academic Significance and Societal Importance of the Research Achievements

骨・軟骨石灰化のおけるアルカリホスファターゼ（ALP）によるリン産生の意義は明らかではない。ヒト間葉系幹細胞やヒト低ホスファターゼ患者由来誘導骨芽細胞を用いた石灰化実験によって、ALP活性、リン濃度、ピロリン酸濃度、リン/ピロリン酸濃度比が骨石灰化や骨芽細胞分化マーカーに影響を与える可能性が示唆された。成長障害を伴う骨や軟骨の石灰化障害、骨脆弱性疾患の病態解明や新規治療法の開発に寄与する可能性がある。

Research Products

• [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] Hypophosphatasia in Japan: ALPL Mutation Analysis in 98 Unrelated Patients (2020)
  • Author(s): Michigami T, Tachikawa K, Yamazaki M, Kawai M, Kubota T, Ozono K
  • Journal Title: Calcif Tissue Int Volume: 106 Issue: 3 Pages: 221-231
  • DOI: 10.1007/s00223-019-00626-w
  • Peer Reviewed / Open Access
• [Journal Article] Japanese nationwide survey of hypophosphatasia reveals prominent differences in genetic and dental findings between odonto and non-odonto types (2019)
  • Author(s): Okawa Rena、Kokomoto Kazuma、Kitaoka Taichi、Kubota Takuo、Watanabe Atsushi、Taketani Takeshi、Michigami Toshimi、Ozono Keiichi、Nakano Kazuhiko
  • Journal Title: PLOS ONE Volume: 14 Issue: 10 Pages: e0222931-e0222931
  • DOI: 10.1371/journal.pone.0222931
  • 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
• [Journal Article] Genetic correction of induced pluripotent stem cells mediated by transcription activator-like effector nucleases targeting ALPL recovers enzyme activity and calcification in vitro (2019)
  • Author(s): Nakano Chiho、Kitabatake Yasuji、Takeyari Shinji、Ohata Yasuhisa、Kubota Takuo、Taketani Ken、Kogo Mikihiko、Ozono Keiichi
  • Journal Title: Molecular Genetics and Metabolism Volume: 127 Issue: 2 Pages: 158-165
  • DOI: 10.1016/j.ymgme.2019.05.014
  • Peer Reviewed
• [Journal Article] Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X‐Linked Hypophosphatemia: A Phase 3, Single‐Arm, International Trial (2019)
  • Author(s): Insogna Karl L、Rauch Frank、Kamenicky Peter、Ito Nobuaki、Kubota Takuo、Nakamura Akie、Zhang Lin、Mealiffe Matt、San Martin Javier、Portale Anthony A
  • Journal Title: Journal of Bone and Mineral Research Volume: 34 Issue: 12 Pages: 2183-2191
  • DOI: 10.1002/jbmr.3843
  • Peer Reviewed
• [Journal Article] Continued Beneficial Effects of Burosumab in Adults with X-Linked Hypophosphatemia: Results from a 24-Week Treatment Continuation Period After a 24-Week Double-Blind Placebo-Controlled Period (2019)
  • Author(s): Portale AA, Carpenter TO, Brandi ML, Briot K, Cheong HI, Cohen-Solal M, Crowley R, Jan De Beur S, Eastell R, Imanishi Y, Imel EA, Ing S, Ito N, Javaid M, Kamenicky P, Keen R, Kubota T, et al.
  • Journal Title: Calcif Tissue Int Volume: 105 Issue: 3 Pages: 271-284
  • DOI: 10.1007/s00223-019-00568-3
• [Presentation] くる病 (2019)
  • Author(s): 窪田拓生
  • Organizer: 第92回日本内分泌学会学術総会
  • Invited
• [Presentation] 低リン血症性疾患の病態と診断～FGF23測定の有用性～ (2019)
  • Author(s): 窪田拓生
  • Organizer: 第37回日本骨代謝学会学術集会
  • Invited
• [Presentation] Biochemical and genetic analysis in patients with odontohypophosphatasia in Japan (2019)
  • Author(s): Kubota T, Ohata Y, Ishihara Y, Fujiwara M, Takeyari S, Yamamoto K, Nakano Y, Miyata K, Nakayama H, Kitaoka T, Okawa R, Nakano K, Akiyama T, Ozono K
  • Organizer: 9th International Conference on Children's Bone Health
  • Int'l Joint Research
• [Presentation] Mutation analysis of the PHEX gene and genotype-phenotype correlation in 37Japanese patients X-linked hypophosphatemic rickets (2019)
  • Author(s): Ohata Y, Kubota T, Takeyari S, Kitaoaka T, Nakano Y, Miyata K, Yamada C, Ozono K, Ishihara Y, Nakayama H, Yamamoto K, Fujiwara M, Yamamoto K, Michigami T, Mabe H, Yamaguchi T, Matsui K, Tamada I, Namba N, Yamamoto A, Etoh J, Kawaguchi A
  • Organizer: 2019 Annual Meeting of American Society for Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] 日本人低ホスファターゼ症患者52例のベースラインの検討 ―ALP酵素補充療法特定使用成績調査より― (2019)
  • Author(s): 窪田拓生, 藤原幾磨, 道上敏美, 渡邉 淳, 難波範行, 鬼頭浩史, 室月 淳, 杉山裕一朗, 仲野和彦, 笹谷晴恵, 長谷川航, 別所友子, 澤井英明, 大薗恵一
  • Organizer: 第53回日本小児内分泌学会学術集会
• [Presentation] 歯限局型低ホスファターゼ症の生化学的・遺伝学的検討 (2019)
  • Author(s): 窪田拓生, 大幡泰久, 石原康貴, 藤原 誠, 武鑓真司, 山本賢一, 中野由佳子, 中山尋文, 北岡太一, 大薗恵一
  • Organizer: 第37回日本骨代謝学会学術集会
• [Presentation] X連鎖性低リン血症性くる病に併存するhypovitaminosis Dの検討 (2018)
  • Author(s): 中山尋文・宮田京・中野由佳子・山本賢一・武鑓真司・大幡泰久・北岡太一・窪田拓生・大薗恵一・道上敏美・山本勝輔
  • Organizer: 第91回日本内分泌学会学術総会
• [Presentation] 低ホスファターゼ症患者由来iPS細胞におけるTALENを用いた遺伝子変異修復 (2018)
  • Author(s): 中野知帆、北畠康司、武鑓真司、大幡泰久、窪田拓生、竹谷健、古郷幹彦、大薗恵一
  • Organizer: 第52回日本小児内分泌学会学術集会
• [Presentation] X連鎖性低リン血症性くる病患者における血清FGF23濃度と関連するパラメータの検討 (2017)
  • Author(s): 5.窪田拓生、山本景子、宮田京、武鑓真司、山本賢一、中山尋文、藤原誠、北岡太一、高桑聖、大薗恵一
  • Organizer: 第90回日本内分泌学会学術集会