Bone-specific action of parathyroid hormone on membrane transporters and enzymes involved in phosphate ion supplement

• Project/Area Number: 18H02964
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 57010:Oral biological science-related
• Research Institution: Hokkaido University
• Principal Investigator: AMIZUKA Norio 北海道大学, 歯学研究院, 教授 (30242431)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2018: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: 石灰化 / リン酸供与膜輸送体 / 副甲状腺ホルモン / 骨芽細胞 / 微細構造

Outline of Final Research Achievements

The purpose of this study is to evaluate if the synthesis and supply of phosphate ions －a constituent of calcified bone matrix－ is regulated by serum concentration of parathyroid hormone (PTH). PTH-administered mice showed the increased expression of TNAP, ENPP1, ANK, PHOSPHO1 and SIBLING family, consequently resulting in highly-calcified bone matrix. In contrast, NaPiIIa/IIc mice bearing hypophosphatemia revealed no change of TNAP, ENPP1, ANK, PHOSPHO1 genes and SIBLING family, showing less amount of bone volume. Hyp mice － another hypophosphatemia model due to mutation in Phex－demonstrated huge areas of uncalcified bone matrix. Taken together, it seems likely that PTH increases the synthesis and supply of phosphate ions in bone, while calcification in bone matrix is regulated by Phex/SIBLING family.

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会を迎えた現在、骨をはじめとする運動器の健康維持はヒトの健康寿命を延ばすうえで大きく貢献すると思われる。特に、骨強度に深く関与する骨基質石灰化は、血清カルシウム(Ca)とリンによって規定されると考えられているが、血清Ca濃度はほぼ一定に維持されていることから、血清リン濃度変化による骨基質石灰化が注目を浴びている。特に、骨基質石灰化において、骨代謝に影響を与える副甲状腺ホルモンによるリン酸供与作用の検索は、基礎研究から骨基質石灰化のメカニズムを解明することに繋がり、正常あるいは病的石灰化において重要な情報を与えると考えられる。

Research Products

• [Journal Article] Frequent administration of abaloparatide shows greater gains in bone anabolic window and bone mineral density in mice: A comparison with teriparatide. (2021)
  • Author(s): Makino A., Hasegawa T., Takagi H., Takahashi Y., Hase N., Amizuka N.
  • Journal Title: Bone. Volume: 142巻 Pages: 115651-115651
  • DOI: 10.1016/j.bone.2020.115651
  • Peer Reviewed
• [Journal Article] Altered immunolocalization of FGF23 in murine femora metastasized with human breast carcinoma MDA-MB-231 cells. (2021)
  • Author(s): Yokoyama A., Hasegawa T., Hiraga T., Yamada T., Yimin, Hongo H., Yamamoto T., Abe M., Yoshida T., Imanishi Y., Kuroshima S., Sasaki M., Freitas PHL., Li M., Amizuka N., Yamazaki Y.
  • Journal Title: J Bone Miner Metab. Volume: 印刷中 Issue: 5 Pages: 810-823
  • DOI: 10.1007/s00774-021-01220-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Osteocalcin is necessary for the alignment of apatite crystallites, but not glucose metabolism, testosterone synthesis, or muscle mass (2020)
  • Author(s): Moriishi Takeshi、Ozasa Ryosuke、Ishimoto Takuya、Nakano Takayoshi、Hasegawa Tomoka、Miyazaki Toshihiro、Liu Wenguang、Fukuyama Ryo、Wang Yuying、Komori Hisato、Qin Xin、Amizuka Norio、Komori Toshihisa
  • Journal Title: PLOS Genetics Volume: 16 Issue: 5 Pages: 1008586-1008586
  • DOI: 10.1371/journal.pgen.1008586
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Osteocytic Osteolysis in PTH-treated Wild-type and Rankl-/- Mice Examined by Transmission Electron Microscopy, Atomic Force Microscopy, and Isotope Microscopy. (2020)
  • Author(s): Hongo H., Hasegawa T., Saito M., Tsuboi K., Yamamoto T., Sasaki M., Abe M., Freitas PHL., Yurimoto H., Udagawa N., Li M., Amizuka N.
  • Journal Title: J Histochem Cytochem. Volume: 68 Issue: 10 Pages: 651-668
  • DOI: 10.1369/0022155420961375
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Immunocytochemical assessment of cell differentiation of podoplanin-positive osteoblasts into osteocytes in murine bone. (2020)
  • Author(s): Nagai T., Hasegawa T., Yimin, Yamamoto T., Hongo H., Abe M., Yoshida T., Yokoyama A., Freitas PHL., Li M., Yokoyama A., Amizuka N.
  • Journal Title: Histochem Cell Biol. Volume: 155 Issue: 3 Pages: 369-380
  • DOI: 10.1007/s00418-020-01937-y
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intermittent PTH administration increases bone specific-blood vessels and surrounding stromal cells in murine long bones. (2020)
  • Author(s): Zhao S., Hasegawa T., Hongo H., Yamamoto T., Abe M., Yoshida T., Haraguchi M., Freitas PHL., Li M., Tei K., Amizuka N.
  • Journal Title: Calcif Tissue Int. Volume: 108 Issue: 3 Pages: 391-406
  • DOI: 10.1007/s00223-020-00776-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Role of sodium-dependent Pi transporter/Npt2c on Pi homeostasis in klotho knockout mice different properties between juvenile and adult stages. (2020)
  • Author(s): Hanazaki A, Ikuta K, Sasaki S, Sasaki S, Koike M, Tanifuji K, Arima Y, Kaneko I, Shiozaki Y, Tatsumi S, Hasegawa T, Amizuka N, Miyamoto KI, Segawa H.
  • Journal Title: Physiol Rep. Volume: Feb;8(3) Issue: 3 Pages: 1-16
  • DOI: 10.14814/phy2.14324
  • Peer Reviewed / Open Access
• [Journal Article] Osteocalcin is necessary for the alignment of apatite crystallites, but not glucose metabolism, testosterone synthesis, or muscle mass. (2020)
  • Author(s): Moriishi T., Ozasa R., Ishimoto T., Liu W., Hasegawa T., Amizuka N., Komori T.
  • Journal Title: PLOS Genetics. Volume: in press
  • Peer Reviewed
• [Journal Article] Three-dimensional morphology of the Golgi apparatus in osteoclasts: NADPase and arylsulfatase cytochemistry, and scanning electron microscopy using osmium maceration. (2019)
  • Author(s): Yamamoto T., Hasegawa H., Hongo H., Amizuka N.
  • Journal Title: Microscopy Volume: 68巻3号 Issue: 3 Pages: 243-253
  • DOI: 10.1093/jmicro/dfz003
  • Peer Reviewed / Open Access
• [Journal Article] 副甲状腺ホルモン製剤の骨形成作用について (2019)
  • Author(s): 長谷川智香、宮本幸奈、山本知真也、網塚憲生
  • Journal Title: 日本薬理学会雑誌 Volume: 153 Pages: 16-21
  • NAID: 130007556041
  • Peer Reviewed
• [Journal Article] Eldecalcitol Causes FGF23 Resistance for Pi Reabsorption and Improves Rachitic Bone Phenotypes in the Male Hyp Mouse. (2018)
  • Author(s): Kaneko I, Segawa H, Ikuta K, Hanazaki A, Fujii T, Tatsumi S, Kido S, Hasegawa T, Amizuka N, Saito H, Miyamoto KI.
  • Journal Title: Endocrinology Volume: 159(7) Issue: 7 Pages: 2741-2758
  • DOI: 10.1210/en.2018-00109
  • Peer Reviewed / Open Access
• [Journal Article] Histological Effects of the Combined Administration of Eldecalcitol and a Parathyroid Hormone in the Metaphyseal Trabeculae of Ovariectomized Rats (2018)
  • Author(s): Hasegawa T., Yamamoto T., Sakai S., Miyamoto Y., Hongo H., Qiu Z., Abe M., Takeda S., Oda K., Freitas PHL., Li M., Endo K., Amizuka N.
  • Journal Title: Journal of Histochemistry & Cytochemistry Volume: 67 Issue: 3 Pages: 169-184
  • DOI: 10.1369/0022155418806865
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sequential Treatment with Eldecalcitol After PTH Improves Bone Mechanical Properties of Lumbar Spine and Femur in Aged Ovariectomized Rats (2018)
  • Author(s): Sakai S., Hongo H., Yamamoto T., Hasegawa T., Takeda S., Saito H., Endo K., Yogo Y., Amizuka N.
  • Journal Title: Calcified Tissue International Volume: 104 Issue: 3 Pages: 251-261
  • DOI: 10.1007/s00223-018-0497-y
  • Peer Reviewed / Open Access
• [Journal Article] FGF23/klothoシグナルによる基質石灰化制御機構の解明 (2018)
  • Author(s): 長谷川智香、宮本幸奈、邱 紫セン、阿部未来、本郷裕美、網塚憲生
  • Journal Title: 日本骨粗鬆症学会雑誌 Volume: 4 Pages: 134-136
  • Peer Reviewed
• [Presentation] PTH間歇投与マウス大腿骨におけるpodoplanin/PHOSPHO1陽性骨芽細胞の局在 (2021)
  • Author(s): 中島悠斐、山本知真也、本郷裕美、網塚憲生、長谷川智香
  • Organizer: 第126回日本解剖学会総会・全国学術集会/第98回日本生理学会大会合同大会
• [Presentation] Remodeling/Modeling-based bone formationの組織学 (2020)
  • Author(s): 網塚憲生、長谷川智香、本郷裕美、山本知真也
  • Organizer: 第40回日本骨形態計測学会
  • Invited
• [Presentation] 動物モデルを用いた骨組織再生の顕微学的検索 (2020)
  • Author(s): 網塚憲生、長谷川智香
  • Organizer: 公益社団法人日本セラミックス協会第33回秋季シンポジウム
  • Invited
• [Presentation] 骨血管連関からみた骨芽細胞系細胞の分化 (2020)
  • Author(s): 長谷川智香、趙 申、吉野弘菜、阿部未来
  • Organizer: 第62回歯科基礎医学会学術大会
  • Invited
• [Presentation] Abaloparatide promotes bone repair of vertebral defects in an overiectomized rat model of osteoporosis (2020)
  • Author(s): Makino A., Hasegawa T., Takagi H., Takahashi Y., Hase N., Amizuka N.
  • Organizer: World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases 2020
  • Int'l Joint Research
• [Presentation] Abaloparatide promotes bone repair of vertebral defects in an overiectomized rat model of osteoporosis (2020)
  • Author(s): Makino A., Hasegawa T., Takagi H., Takahashi Y., Hase N., Amizuka N.
  • Organizer: The American Society for Bone and Mineral Research 2020 Annual Meeting
  • Int'l Joint Research
• [Presentation] 副甲状腺ホルモン間歇投与による皮質骨多孔化の組織化学的検索 (2020)
  • Author(s): 阿部未来、山本知真也、本郷裕美、網塚憲生、長谷川智香
  • Organizer: 第62 回歯科基礎医学会学術大会
• [Presentation] モデリングおよび骨リモデリング領域の骨芽細胞の活性化における組織細胞学的検索 (2020)
  • Author(s): 阿部未来、長谷川智香、宇田川信之、網塚憲生
  • Organizer: 第38回日本骨代謝学会学術集会
• [Presentation] PTH投与による高骨代謝回転状態でのpodoplanin/PHOSPHO1陽性骨芽細胞の局在 (2020)
  • Author(s): 中嶋悠斐、山本知真也、本郷裕美、網塚憲生、長谷川智香
  • Organizer: 第38回日本骨代謝学会学術集会
• [Presentation] 椎体を欠損させた卵巣摘除ラットにおけるアバロパラチドの骨欠損修復促進作用 (2020)
  • Author(s): 槙野彰人、長谷川智香、網塚憲生
  • Organizer: 第38回日本骨代謝学会学術集会
• [Presentation] 歯科領域の骨再生における細胞学的・微細構造学的検索 －動物モデルの顕微解析 (2020)
  • Author(s): 網塚憲生、本郷裕美、長谷川智香
  • Organizer: 第19回日本再生医療学会総会
  • Invited
• [Presentation] 骨血管連関における細胞間コミュニケーション (2020)
  • Author(s): 長谷川智香、本郷裕美、山本知真也、網塚憲生
  • Organizer: 第125回日本解剖学会総会・全国学術集会
  • Invited
• [Presentation] Histochemical assessment for bone/vascular mineralization of kl/kl and αklotho-/- mice. (2019)
  • Author(s): Hasegawa T.: Yamamoto T., Miyamoto Y., Qiu Z., Hongo H., Amizuka N.
  • Organizer: The 7th Seoul Symposium on Bone Health & the 31th Spring Scientific Congress of the Korean Society for Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] Cellular mechanism of abnormal mineralization of bone and aorta induced by the disrupted function of FGF23/klotho. (2019)
  • Author(s): Hasegawa T., Miyamoto-Takasaki Y., Qiu Z., Yamamoto T., Amizuka N.
  • Organizer: 97thGeneral Session & Exhibition of The International Association for Dental Research (IADR), 48th Annual Meeting of The AADR, 43rd Annual Meeting of THE CADR
  • Int'l Joint Research
• [Presentation] Histochemical assessment of abnormal mineralization in bone and aorta induced by disrupted FGF23/αklotho. (2019)
  • Author(s): Hasegawa T., Yamamoto T., Miyamoto Y., Qiu Z., Hongo H., Amizuka N.
  • Organizer: The American Society for Bone and Mineral Research (ASBMR) 2019Annual Meeting
  • Int'l Joint Research
• [Presentation] The biological effect of bone-specific blood vessels by intermittent PTH administration in mice. (2019)
  • Author(s): Zhao S., Hasegawa T., Tei K., Amizuka N.
  • Organizer: 日本解剖学会第 65 回東北・北海道連合支部学術集会
• [Presentation] 骨粗鬆症モデルラットにおけるエルデカルシトール誘導性ミニモデリングの組織化学的解析 (2019)
  • Author(s): 長谷川智香、山本知真也、本郷裕美、武田 聡、坂井貞興、與語健二、松本義弘、網塚憲生
  • Organizer: 第61回歯科基礎医学会学術大会
• [Presentation] Jansen 型PTH/PTHrP受容体変異トランスジェニックマウスの形態および機能異常解析 (2019)
  • Author(s): 下村-黒木淳子、梨田智子、森田貴雄、大島勇人、網塚憲生
  • Organizer: 第61回歯科基礎医学会学術大会
• [Presentation] Abnormal Mineralization in Bone and Aorta Induced by the Disrupted Function of FGF23/klotho. (2019)
  • Author(s): Hasegawa T., Miyamoto Y., Qiu Z., Yamamoto T., Amizuka N.
  • Organizer: International Collaborative Symposium on Development of Human Resources in Practical Oral Health and Treatment
  • Int'l Joint Research / Invited
• [Presentation] Histological Assessment of Bone Formation Induced by the New Bone Prosthetic Material Contained Phosphorylated-Pullulan. (2019)
  • Author(s): Hasegawa T., Hongo H., Qiu Z., Miyamoto Y., Amizuka N.
  • Organizer: International Collaborative Symposium on Development of Human Resources in Practical Oral Health and Treatment
  • Int'l Joint Research / Invited
• [Presentation] 骨基質石灰化におけるリン-FGF23-Klotho axis (2018)
  • Author(s): 網塚憲生、長谷川智香、邱 紫セン、本郷裕美
  • Organizer: 第63回日本透析医学会学術集会・総会
  • Invited
• [Book] 副甲状腺・骨代謝疾患診療マニュアル改訂第2版 (2019)
  • Author(s): 長谷川智香、宮本幸奈、網塚憲生
  • Total Pages: 264
  • Publisher: 診断と治療社
  • ISBN: 9784787823748
• [Book] 副甲状腺・骨代謝疾患診療マニュアル (2019)
  • Author(s): 長谷川智香、宮本幸奈、網塚憲生
  • Publisher: 診断と治療社
• [Book] CKD-MBD 3rd Edition (2018)
  • Author(s): 網塚憲生、邱 紫セン、長谷川智香
  • Total Pages: 320
  • Publisher: 日本メディカルセンター
  • ISBN: 9784888753081
• [Remarks] 北海道大学大学院歯学研究院 / 大学院歯学院 / 歯学部
  • URL: https://www.den.hokudai.ac.jp/
• [Remarks] 北海道大学大学院歯学研究院 口腔健康科学分野 硬組織発生生物学教室
  • URL: https://www.den.hokudai.ac.jp/anatomy2/hokudai_d/index.html