Study of the FGF23-soluble Klotho axis in bone and dental diseases.

2013 Fiscal Year Final Research Report

• Project/Area Number: 23592701
• 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: YOSHIKO YUJI 広島大学, 医歯薬保健学研究院, 教授 (20263709)
• Co-Investigator(Renkei-kenkyūsha): SUZUKI Atsushi 藤田保健衛生大学, 医学部, 准教授 (90340265) ; UCHIDA Soshi 産業医科大学, 医学部, 准教授 (60330990)
• Project Period (FY): 2011 – 2013
• Keywords: FGF23 / 石灰化 / Phex / ASARM / 骨代謝

Research Abstract

We found that FG23, a phosphaturic factor, inhibits bone formation even though membrane Klotho (mKL), a coreceptor for FGF23 is not expressed in bone. It is known that mKL is cleaved and circulated as soluble KL (sKL). We confirmed that sKL supports the FGF23 effects on bone. Among FGF family members expressed in bone, FGF23, transcriptionally activated by 1,25(OH)2D3, stimulated transient activation of ERK1/2 only in mature steoblasts/osteocytes. This signaling downregulated Phex, with the resultant increase in the accumulation of ASARM peptide in bone. Administration of ASARM peptide decreased bone mineralization without affecting osteoblast proliferation and differentiation. These data describe a novel mechanism by which FGF23 regulates bone formation.

Research Products

• [Journal Article] one of the major anthocyanidins, prevents bone loss through the inhibition of excessive osteoclastogenesis in osteoporpsis model mice (2014)
  • Author(s): Moriwaki Sawako, Suzuki Keiko, Muramatsu Masashi, Nomura Atsushi, Inoue Fuihide, Into Takeshi, Yoshiko Yuji, Niida Shumpei,Delphinidin
  • Journal Title: PLoS One Volume: 9 Pages: e97177
  • DOI: 10.1371/iournal.pone.0097177
  • Peer Reviewed
• [Journal Article] 骨・血管相関とmicro RNA (2014)
  • Author(s): 竹井悠一郎,吉子裕二
  • Journal Title: 臨床化学 Volume: 43 Pages: 106-111
• [Journal Article] The EP4-ERK-dependent pathway stimulates osteo-adipogenic progenitor proliferation resulting in increased adipogenesis in fetal rat calvaria cell cultures (2012)
  • Author(s): Minamizaki Tomoko, Yoshiko Yuji, Yoshioka Hirotaka, KOzai Katsuyuki, Aubin Jane E, Maeda Norihiko
  • Journal Title: Prostaglandins Other Lipid Mediat Volume: 97 Pages: 97-102
  • DOI: 10.1016/j.prostaglandins.2012.01.001
  • Peer Reviewed
• [Journal Article] Incisor snemal formation is impaired in transgenic rats overexpressing the type III NaPi transporter Slc20a1 (2011)
  • Author(s): Yoshioka Hirotaka, Yoshiko Yuji, Minamizak Tomoko, Koma Yoshio, Nobukiyo Asako, Sotomoru Yusuke, Maeda Norihiko
  • Journal Title: Calcified Tissue Int Volume: 89 Pages: 192-202
  • DOI: 10.1007/s00223-011-9506-0
  • Peer Reviewed
• [Presentation] MEPE-ASARM, a substrate of Phex, decreases bone volume independently of serum phosphate levels (2014)
  • Author(s): Sakurai Kaoru,Minamizaki Tomoko, Fujino Yoko, Takei Yuichiro, Yoshioka Hirotaka, Okada Mitsugu, Kozai Katsuyuki, Yoshiko Yuji
  • Organizer: The American Society for Bone Mineral Research 2014 Annual Meeting
  • Place of Presentation: Houston, USA
  • Year and Date: 20140912-14
• [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
  • Place of Presentation: 大阪
  • Year and Date: 20140724-26
• [Presentation] A novel therapeutic approach to abdominal aortic aneurysm through the inhibition of osteoclastogenesis (2013)
  • Author(s): Takei Yuichiro, Yamaguchi Daisuke, Yoshiko Yuji
  • Organizer: 5th Hiroshima Conference on Education and Science in Dentistry
  • Place of Presentation: Hiroshima
  • Year and Date: 20131012-13
• [Presentation] Imaging mass spectrometry-based molecular histology of bone shows the implication of MEPE-ASARM for the Klotho-deficient phenotype (2013)
  • Author(s): Fujino Yoko, Minamizaki Tomoko, Sakurai Kaoru, Irie Yasumasa, Yosioka Hirotaka, Takei Yuichiro, Kozai Katsuyuki, Okada Mitsugu, Yoshiko Yuji
  • Place of Presentation: Baltimore, USA
  • Year and Date: 20131004-07
• [Presentation] (2013)
  • Author(s): Minamizaki Tomoko, Konishi Yukiko, Sakurai Kaoru, Yoshioka Hirotaka, Kozai Katsuyuki, Yoshiko Yuji
  • Organizer: 2nd Joint Meeting of the International Bone and Mineral Society and the Japanese Society for Bone and Mineral Research
  • Place of Presentation: Kobe
  • Year and Date: 20130528-0601
• [Presentation] Transient but not constitutive activation of ERK is necessary for the unique actions of FGF23 in bone (2012)
  • Author(s): Minamizaki Tomoko, Konishi Yukiko, Yoshioka Hirotaka, Kozai Katsuyuki, Yoshiko Yuji
  • Organizer: The American Society for Bone and Mineral Research 2012 Annual Meeting
  • Place of Presentation: Minneapolis, USA
  • Year and Date: 20121012-15
• [Presentation] MEPE=derived phosphorylated ASARM is involved in FGF23/soluble Klotho-dependent hypomineralization (2011)
  • Author(s): Konishi Yukiko, Yoshiko Yuji, MInamizaki Tomoko, Yoshioka Hirotaka, Kozai Katsuyuki, Aubin Jane E, Maeda Norihiko
  • Organizer: The American Society for Bone and Mineral Research 2012 Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 20110916-19
• [Presentation] MEPE由来リン酸化ASARMとPhexはFGF23/可溶型Klothoによる石灰化の負の調節系と関連する (2011)
  • Author(s): 小西有希子,吉子裕二,南崎朋子,吉岡広陽,香西克之,前田憲彦
  • Organizer: 第29回日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 20110728-30
• [Presentation] FGFシグナルによる石灰化調節:FGF23-Phex経路を中心として (2011)
  • Author(s): 南崎朋子,吉子裕二,小西有希子,吉岡広陽,香西克之,前田憲彦
  • Organizer: 第29回日本骨代謝学会
  • Place of Presentation: 大阪
  • Year and Date: 20110728-30
• [Patent(Industrial Property Rights)] リン酸化ペプチド、硬組織および/または異所性石灰化抑制剤,抗体ならびに硬組織および/または異所性石灰化促進剤 (2011)
  • Inventor(s): 吉子裕二,南崎朋子,吉岡広陽,平田伊佐雄,香西克之,前田憲彦,渡邊和晃,清藤勉
  • Industrial Property Rights Holder: 広島大学,(株)ラフィーネインターナショナル,(株)免疫生物研究所種類
  • Industrial Property Rights Type: 特願
  • Industrial Property Number: 2011-150487
  • Filing Date: 2011-07-06
  • Overseas