The roles of downstream factor(s) of cancer cell-derived Klotho on bone mineralization

• Project/Area Number: 25462858
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Morphological basic dentistry
• Research Institution: Hiroshima University
• Principal Investigator: MINAMIZAKI TOMOKO 広島大学, 医歯薬保健学研究院, 助教 (30452593)
• Co-Investigator(Kenkyū-buntansha): YOSHIKO YUJI 広島大学, 大学院医歯薬保健学研究院, 教授 (20263709)
• Co-Investigator(Renkei-kenkyūsha): FUTAMURA MANABU 岐阜大学, 医学部, 准教授 (10415515) ; KOZAI KATSUYUKI 広島大学, 大学院医歯薬保健学研究院, 教授 (10178212)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Klotho / FGF23 / 骨代謝 / リン代謝 / 骨転移 / 細胞・組織 / がん細胞

Outline of Final Research Achievements

Soluble Klotho (sKL) was detected in the several cancer cell lines and stimulated ERK signaling in vitro in the combination with FGF23 which is derived from bone. However, sKL-mediated ERK signaling was tissue-specifically regulated because of the presence of the protease(s) by which FGF23 was processed.
Downstream factor of sKL and FGF23, X, was identified by DNA microarray. X inhibited bone matrix mineralization in vivo and in vitro, but did not affect on proliferation and differentiation in both osteoblast and osteoclast cell cultures. X was strongly detected in bone matrix. osteoblasts and osteocytes with immunohistochemistry by anti-X polyclonal antibody.

Research Products

• [Journal Article] The bioactive acidic serine- and aspartate-rich motif Peptide. (2015)
  • Author(s): Minamizaki T, Yoshiko Y.
  • Journal Title: Curr Protein Pept Sci. Volume: 16 Issue: 3 Pages: 196-202
  • DOI: 10.2174/1389203716666150206122839
  • NAID: 120006879596
  • Peer Reviewed / Open Access
• [Journal Article] Functional diversity of fibroblast growth factors in bone formation. (2015)
  • Author(s): Takei Y, Minamizaki T, Yoshiko Y.
  • Journal Title: Int J Endocrinol. Volume: 2015 Pages: 729352-729352
  • DOI: 10.1155/2015/729352
  • NAID: 120006824054
  • Peer Reviewed / Open Access
• [Presentation] MEPE-ASARM, a substrate of the neutral endopeptidase PHEX involved in rickets/osteomalacia, acts as an inhibitor of bone formation. (2015)
  • Author(s): Sakurai K, Minamizaki T, Hayashi I, Yoshioka H, Takei Y, Kozai K, Yoshiko Y
  • Organizer: 6th Hiroshima Conference on Education and Science in Dentistry
  • Place of Presentation: Hiroshima
  • Year and Date: 2015-10-23
  • Int'l Joint Research
• [Presentation] Nano-CT Analysis of Osteocyte Anomalies in Klotho-deficient Mice. (2015)
  • Author(s): Minamizaki T, Sakurai K, Yoshioka H, Takei Y, Kozai K, Yoshiko Y
  • Organizer: The American Society for Bone and Mineral Research 2015 Annual Meeting
  • Place of Presentation: Seattle, USA
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] Klotho欠損マウス腎臓のイメージング質量分析 (2014)
  • Author(s): 藤野陽子、南崎朋子、宮脇聡子、川上朝子、宮地孝明、櫻井薫、竹井悠一郎、吉岡広陽、香西克之、岡田貢、吉子裕二
  • Organizer: 日本解剖学会第69回中国・四国支部学術集会
  • Place of Presentation: 広島
  • Year and Date: 2014-10-25 – 2014-10-26
• [Presentation] 骨基質タンパクMEPE-由来ASARMは血中リン濃度非依存的に骨量を減少させる (2014)
  • Author(s): 櫻井薫、南崎朋子、川本真貴子、藤野陽子、竹井悠一郎、吉岡広陽、岡田 貢、香西克之、吉子裕二
  • Organizer: 日本解剖学会第69回中国・四国支部学術集会
  • Place of Presentation: 広島
  • Year and Date: 2014-10-25 – 2014-10-26
• [Presentation] MEPE-ASARM, a substrate of Phex, decreases bone volume independently of serum phosphate levels (2014)
  • Author(s): Sakurai K, Minamizaki T, Yoshioka H, Takei Y, Kozai K, Yoshiko Y
  • Organizer: The American Society for Bone and Mineral Research 2014 Annual Meeting
  • Place of Presentation: Houston（USA）
  • Year and Date: 2014-09-12 – 2014-09-15
• [Presentation] Phexの基質MEPE-ASARMは血中リン濃度非依存的に骨量を減少させる (2014)
  • Author(s): 櫻井薫、南崎朋子、吉岡広陽、竹井悠一郎、香西克之、吉子裕二
  • Organizer: 日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-07-24 – 2014-07-26
• [Presentation] MEPE=ASARM, a substrate of Phex, decreases bone volume independently ofserum phosphate levels. (2014)
  • Author(s): Sakurai K, Minamizaki T, Fujino Y, Takei Y, Yoshioka H, Okada M, Kozai K, Yoshiko Y
  • Organizer: The American Society for Bone and Mineral Research 2014 Annual Meeting
  • Place of Presentation: Houston, TX, USA
• [Presentation] Soluble Klotho does not rescue but rather exaggerates skeletal defects in klotho-deficient mice. (2013)
  • Author(s): Minamizaki T, Konishi Y, Sakurai K, Yoshioka H, Kozai K, Yoshiko Y
  • Organizer: 2nd Joint Meeting of the International Bone and Mineral Society and the Japanese Society for Bone and Mineral Research
  • Place of Presentation: Kobe, Japan
• [Presentation] Imaging mass spectrometry-based molecular histology of bone shows the implication of MEPE-ASARM for the Klotho-deficient phonotype. (2013)
  • Author(s): Fujino Y, Minamizaki T, Sakurai K, Irie Y, Yoshioka H, Takei Y, Kozai K, Okada M, Yoshiko Y
  • Organizer: The American Society for Bone and Mineral Research 2013 Annual Meeting
  • Place of Presentation: Baltimore, MD, USA