Regulation of bone minerals by FGF23/klotho axis related to osteocytic function

• Project/Area Number: 24390406
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Morphological basic dentistry
• Research Institution: Hokkaido University
• Principal Investigator: AMIZUKA Norio 北海道大学, 歯学研究科(研究院), 教授 (30242431)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000); Fiscal Year 2014: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2012: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: 骨細胞 / FGF23 / klotho / 骨基質 / 石灰化 / aklotho-/-マウス / kl/klマウス / 細胞・組織 / 細胞組織

Outline of Final Research Achievements

Signaling linked to αklotho/FGF23 is predominantly found in the proximal renal tubules, where it inhibits Pi reabsorption and 1α-hydroxylase activity. Therefore disrupted function of FGF23/αklotho in kl/kl mice and αklotho-deficient (αklotho-/-) mice results in hyperphosphatemia and hypercalcemia. Despite of elevated concentration of serum Pi, bone minerals around several osteocytes were disappeared. Kl/kl mice fed with low Pi diet showed improved bone matrix, but, αklotho-/- mice still demonstrated patched unmineralized areas in the periphery of the osteocytes. In the kidney of kl/kl mice fed with low Pi diet showed increased expression of αklotho. Therefore, it seems likely that improved histology in bone in kl/kl mice may be due to increased expression of αklotho, but not normalized concentration of serum Pi.

Research Products

• [Journal Article] Local administration of calcitriol positively influences bone remodeling and maturation during restoration of mandibular bone defects in rats. (2015)
  • Author(s): Liu H., Cui J., Feng W., Lv S., Du J., Sun J., Han X., Wang Z., Lu X., Yimin., Oda K., Amizuka N., Li M.
  • Journal Title: Mater Sci Eng C Mater Biol Appl. Volume: 49 Pages: 14-24
  • DOI: 10.1016/j.msec.2014.12.064
  • Peer Reviewed
• [Journal Article] Osteoblast-Specific γ-Glutamyl Carboxylase-Deficient Mice Display Enhanced Bone Formation with Aberrant Mineralization. (2015)
  • Author(s): Azuma K, Shiba S, Hasegawa T, Ikeda K, Urano T, Horie-Inoue K, Ouchi Y, Amizuka N, Inoue S
  • Journal Title: J Bone Miner Res. Volume: 未定 Issue: 7 Pages: 1245-1254
  • DOI: 10.1002/jbmr.2463
  • Peer Reviewed / Open Access
• [Journal Article] Gamma-Glutamyl carboxylase in osteoblasts regulates glucose metabolism in mice. (2014)
  • Author(s): Siba S, Ikeda K, Azuma K, Hasegawa T, Amizuka N, Horie-Inoue K, Inoue S
  • Journal Title: Biochem Biophys Res Commun. Volume: 24;453(3) Issue: 3 Pages: 350-355
  • DOI: 10.1016/j.bbrc.2014.09.091
  • Peer Reviewed / Open Access
• [Journal Article] Vitamin K2 biosynthetic enzyme, UBIAD1 is essential for embryonic development of mice. (2014)
  • Author(s): Nakagawa K, Sawada N, Hirota Y, Uchino Y, Suhara Y, Hasegawa T, Amizuka N, Okamoto T, Tsugawa N, Kamao M, Funahashi N, Okano T
  • Journal Title: PLoS ONE. Volume: 15;9(8) Issue: 8 Pages: e104078-e104078
  • DOI: 10.1371/journal.pone.0104078
  • Peer Reviewed / Open Access
• [Journal Article] Altered distribution of bone matrix proteins and defective bone mineralization in klotho-deficient mice (2013)
  • Author(s): Sasaki M., Hasegawa T., Yamada T., Hongo H., Freitas PHL., Suzuki R., Yamamoto T., Tabata C, , Toyosawa S., Yamamoto T., Oda K., Li M., Inoue N, , Amizuka N.
  • Journal Title: Bone Volume: 57(1) Issue: 1 Pages: 206-219
  • DOI: 10.1016/j.bone.2013.08.008
  • Peer Reviewed
• [Journal Article] Histochemical examination of vascular medial calcification of aorta in klotho-deficient mice. (2013)
  • Author(s): Hasegawa T., Sasaki M., Yamada T., Ookido I., Yamamoto T., Hongo H., Yamamoto T., Oda K., Yokoyama K., Amizuka N.
  • Journal Title: J Oral Biosci. Volume: 55 Pages: 10-15
  • Peer Reviewed
• [Journal Article] Histological examination on osteoblastic activities in the alveolar bone of transgenic mice with induced ablation of osteocytes. (2013)
  • Author(s): Li M., Hasegawa T., Hongo H., Tatsumi S., Liu Z., Guo Y., Sasaki M., Tabata C., Yamamoto T., Ikeda K., Amizuka N.
  • Journal Title: Histology and Histopathol. Volume: 28 Pages: 327-335
  • Peer Reviewed
• [Journal Article] Histological examination on osteoblastic activities in the alveolar bone of transgenic mice with induced ablation of osteocytes (2013)
  • Author(s): Li M, Amizuka N., et al.
  • Journal Title: Histology and Histopathology Volume: (in press)
  • Peer Reviewed
• [Journal Article] Histological assessment for vascular calcification (2013)
  • Author(s): Hasegawa T, Amizuka N., et al.
  • Journal Title: J Oral Biosci Volume: (in press)
  • Peer Reviewed
• [Journal Article] Morphological aspects on osteocytic function on bone mineralization. (2013)
  • Author(s): Sasaki M, Amizuka N., et al.
  • Journal Title: Oral Science International Volume: 9 Pages: 1-8
  • Peer Reviewed
• [Presentation] アレンドロネート連日投与中・投与中止後における骨の細胞群における組織化学的変化． (2014)
  • Author(s): 坪井香奈子、佐々木宗輝、長谷川智香、虎谷彌、織田公光、北川善政、網塚憲生
  • Organizer: 第56回歯科基礎医学会学術大会・総会
  • Place of Presentation: 福岡国際会議場（福岡県・福岡市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] αklotho-/-マウスおよびkl/klマウスの下顎臼歯部歯周組織における組織化学的解析． (2014)
  • Author(s): 彦根久美子、長谷川智香、佐々木宗輝、本郷裕美、土屋恵李佳、虎谷彌、織田公光、飯田順一郎、網塚憲生
  • Organizer: 第56回歯科基礎医学会学術大会・総会
  • Place of Presentation: 福岡国際会議場（福岡県・福岡市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Histopathological Examination on Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ). (2014)
  • Author(s): Amizuka N., Tsuboi K., Hasegawa T., Yamamoto T., Yokoyama A., Shindo M., Kitagawa Y.
  • Organizer: The 9th Scientific Meeting of the Asian Academy of Osseointegration
  • Place of Presentation: 札幌市教育文化会館（北海道・札幌市）
  • Year and Date: 2014-07-04 – 2014-07-05
  • Invited
• [Presentation] Localization of 15N-minodronate by Isotope Microscopy and Histochemical Assessment for the Biological Effects of Minodronate to Bone Cells in Mice. (2014)
  • Author(s): Amizuka N., Sasaki M., Kobayashi Y., Hongo H., Yamamoto T., Hasegawa T., Yurimoto H.
  • Organizer: SISS-16
  • Place of Presentation: 北海道大学（北海道・札幌市）
  • Year and Date: 2014-06-19 – 2014-06-20
  • Invited
• [Presentation] 骨基質石灰化の形態学 (2014)
  • Author(s): 網塚憲生
  • Organizer: 第３４回日本骨形態計測学会
  • Place of Presentation: さっぽろ芸文館（北海道・札幌市）
  • Year and Date: 2014-06-12 – 2014-06-14
• [Presentation] Alterations of bone matrix surrounding osteocytes and theirlacunae induced by administration of parathyroid hormone in mice. (2014)
  • Author(s): Hongo H.
  • Organizer: IBMS Herbert Fleisch Workshop, Brugge, Belgium
  • Place of Presentation: NovotelBrusselsGrandPlace（Belgium）
  • Invited
• [Presentation] オーバービュー： 骨の司令塔－骨細胞－． サテライトシンポジウム12-1 「骨細胞のバイオロジー」 (2013)
  • Author(s): 網塚憲生、宮本幸奈、本郷裕美、佐々木宗輝、長谷川智香
  • Organizer: 第55回歯科基礎医学会学術大会・総会
  • Place of Presentation: 岡山コンベンションセンター（岡山市)
  • Invited
• [Presentation] 副甲状腺ホルモン投与による骨細胞性骨溶解に関する微細構造学的検索． (2013)
  • Author(s): 本郷裕美、山田珠希、山本知真也、中野貴由、宇田川信之、網塚憲生
  • Organizer: 第33回日本骨形態計測学会
  • Place of Presentation: 岡山コンベンションセンター（岡山市)
• [Presentation] klotho欠損マウスにおける骨・血管石灰化のカルシウムパラドックス (2012)
  • Author(s): 網塚憲生, 他
  • Organizer: 日本顕微鏡学会第68回学術講演会
  • Place of Presentation: つくば国際会議場(つくば市)
• [Book] 口腔組織発生学 第２版（脇田 稔、前田健康、中村浩彰、網塚憲生 編） (2015)
  • Author(s): 網塚憲生
  • Total Pages: 369
  • Publisher: 医歯薬出版株式会社
• [Book] イラストで徹底理解する 骨疾患キーワード辞典 (2015)
  • Author(s): 網塚憲生、長谷川智香
  • Publisher: 羊土社
• [Book] 口腔科学「骨の解剖生理」 (2014)
  • Author(s): 網塚憲生
  • Total Pages: 1072
  • Publisher: 朝倉書院（監修：戸塚靖則、高戸 毅）
• [Remarks] 北海道大学大学院歯学研究科口腔健康科学講座硬組織発生生物学教室
  • URL: http://www.den.hokudai.ac.jp/anatomy2/hokudai_d/index.html