Mechanism Underlying the Responsiveness to the Extracellular Phosphate and the Factors which Influence the Sensitivity to FGF23

• Project/Area Number: 20590986
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Research Institute, Osaka Medical Center for Maternal and Child Health
• Principal Investigator: MICHIGAMI Toshimi Research Institute, Osaka Medical Center for Maternal and Child Health, 環境影響部門, 部長 (00301804)
• Co-Investigator(Renkei-kenkyūsha): YAMAZAKI Miwa 地方独立行政法人大阪府立病院機構大阪府立母子保健総合医療センター(研究所), 環境影響部門, 流動研究員 (50455549)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 無機リン酸 / FGF23 / Klotho / シグナル伝達 / ナトリウム / リン酸共輸送担体 / ナトリウム・リン酸共輸送担体 / Klnotho

Research Abstract

Phosphorus is a critical element involved in various biological processes, and organisms possess a system for its homeostasis. However, the mechanism for sensing the excess or shortage of phosphate remains unclear. In this study, we examined the responsiveness of the kidney-derived cell line to extracellular phosphate, and found that increased extracellular phosphate induced the activation of Raf/MEK/ERK pathway leading to altered gene expression. In addition, we revealed that the type III sodium/phosphate co-transporter PiT-1 as well as FGF receptor were involved in the responsiveness of the cells to increased extracellular phosphate. Signaling triggered by an increase in extracellular phosphate shared the same downstream cascade as FGF23 signaling, suggesting that extracellular phosphate itself might influence the sensitivity to FGF23. In conditions with abnormal levels of serum phosphate such as chronic kidney disease, the responsiveness of renal tubules to FGF23 might be altered.

Research Products

• [Journal Article] Cellular ATP synthesis mediated by type III sodium-dependent phosphate transporter Pit-1 is critical to chondrogenesis. (2011)
  • Author(s): Sugita A, Kawai S, Hayashibara T, Amano A, Ooshima T, Michigami T, Yoshikawa H, Yoneda T.
  • Journal Title: J Biol Chem 286 Pages: 3094-3103
  • Peer Reviewed
• [Journal Article] Cellular ATP synthesis mediated by type III sodium-dependent phosphate transporter Pit-1 is critical to chondrogenesis. (2011)
  • Author(s): Sugita A, et al.
  • Journal Title: J Biol Chem Volume: 286 Pages: 3094-3103
  • Peer Reviewed
• [Journal Article] Both FGF23 and extracellular phosphate activate Raf/MEK/ERK pathway via FGF receptors in HEK293 cells. (2010)
  • Author(s): Yamazaki M, Ozono K, Okada T, Tachikawa K, Kondou H, Ohata Y, Michigami T.
  • Journal Title: J Cell Biochem 111 Pages: 1210-1221
  • Peer Reviewed
• [Journal Article] Signaling of extracellular inorganic phosphate up-regulates cyclin D1 expression in proliferating chondrocytes via the Na^+/Pi cotransporter Pit-1 and Raf/MEK/ERK pathway. (2010)
  • Author(s): Kimata M, Michigami T, Tachikawa K, Okada T, Koshimizu T, Yamazaki M, Kogo M, Ozono K.
  • Journal Title: Bone 47 Pages: 938-947
  • Peer Reviewed
• [Journal Article] Clinical characteristics of perinatal lethal hypophosphatasia : a report of 6 cases. (2010)
  • Author(s): Nakamura-Utsunomiya A, Okada S, Hara K, Miyagawa S, Takeda K, Fukuhara R, Nakata Y, Hayashidani M, Tachikawa K, Michigami T, Ozono K, Kobayashi M
  • Journal Title: Clin Pediatr Endocrinol 19 Pages: 7-13
  • Peer Reviewed
• [Journal Article] Signaling of extracellular inorganic phosphate up-regulates cyclin D1 expression in proliferating chondrocytes via the Na^+/Pi cotransporter Pit-1 and Raf/MEK/ERK pathway. (2010)
  • Author(s): Kimata M, et al.
  • Journal Title: Bone Volume: 47 Pages: 938-947
  • Peer Reviewed
• [Journal Article] Both FGF23 and extracellular phosphate activate Raf/MEK/ERK pathway via FGF receptors in HEK293 cells. (2010)
  • Author(s): Yamazaki M, et al.
  • Journal Title: J Cell Biochem Volume: 111 Pages: 1210-1221
  • Peer Reviewed
• [Journal Article] Czech dysplasia occurring in a Japanese family. (2009)
  • Author(s): Matsui Y, Michigami T, Tachikawa K, Yamazaki M, Kawabata H, Nishimura G.
  • Journal Title: Am J Med Genet A 49A Pages: 2285-2289
  • Peer Reviewed
• [Journal Article] Oncogenic nucleoporin CAN/Nup214 interacts with vitamin D receptor and modulates its function. (2009)
  • Author(s): Miyauchi Y, Sakaguchi N, Okada T, Makishima M, Ozono K, Michigami T.
  • Journal Title: J Cell Biochem 106 Pages: 1090-1101
  • Peer Reviewed
• [Journal Article] Severe arterial hypertension : a possible complication of McCune-Albright syndrome. (2009)
  • Author(s): Ohata Y, Yamamoto T, Mori I, Kikuchi T, Michigami T, Imanishi Y, Satomura K, Ida S, Ozono K.
  • Journal Title: Eur J Pediatr 168 Pages: 871-876
  • Peer Reviewed
• [Journal Article] Oncogenic nucleoporin CAN/Nup214 interacts with vitamin D receptor and modulates its function. (2009)
  • Author(s): Miyauchi Y, et al.
  • Journal Title: J Cell Biochem 168 Pages: 1090-1101
  • Peer Reviewed
• [Journal Article] Czech dysplasia occurring in a Japanese family. (2009)
  • Author(s): Matsui Y, et al.
  • Journal Title: Am J Med Genet A 49A Pages: 2285-2289
  • Peer Reviewed
• [Journal Article] Wnt signaling in bone metabolism. (2009)
  • Author(s): Kubota T, et al.
  • Journal Title: J Bone Miner Metab 27 Pages: 265-271
  • Peer Reviewed
• [Journal Article] An Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd. (2008)
  • Author(s): Kubota T, Michigami T, Sakaguchi N, Kokubu C, Suzuki A, Namba N, Sakai N, Nakajima S, Imai K, Ozono K.
  • Journal Title: J Bone Miner Res 23 Pages: 1661-1671
  • Peer Reviewed
• [Journal Article] Causes and differential diagnosis of hypocalcemia-recommendation proposed by expert panel supporeted by Ministry of Health, Labour and Welfare, Japan. (2008)
  • Author(s): Fukumoto S, Namba N, Ozono K, Yamauchi M, Sugimoto T, Michigami T, Tanaka H, Inoue D, Minagawa M, Endo I, Matsumoto T.
  • Journal Title: Endocr J 55 Pages: 784-794
  • Peer Reviewed
• [Journal Article] Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients. Proposal of diagnostic criteria using FGF23 measurement. (2008)
  • Author(s): Endo I, Fukumoto S, Ozono K, Namba N, Tanaka H, Inoue D, Minagawa M, Sugimoto T, Yamauchi M, Michigami T, Matsumoto T.
  • Journal Title: Bone 42 Pages: 1235-1239
  • Peer Reviewed
• [Journal Article] PTH/cAMP/PKA signaling facilitates canonical Wnt signaling via inactivation of glycogen synthase kinase-3β in osteoblastic Saos-2 cells. (2008)
  • Author(s): Suzuki A, Ozono K, Kubota T, Kondou H, Tachikawa K, Michigami T.
  • Journal Title: J Cell Biochem 104 Pages: 314-317
  • Peer Reviewed
• [Journal Article] An Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd (2008)
  • Author(s): Kubota T, et al.
  • Journal Title: J Bone Miner Res 23 Pages: 1661-1671
  • Peer Reviewed
• [Journal Article] Causes and differential diagnosis of hypocalcemia -recommendation proposed by expert panel supporeted by Ministry of Health, Labour and Welfare, Japan (2008)
  • Author(s): Fukumoto S, et al.
  • Journal Title: Endocrine J 55 Pages: 784-794
  • Peer Reviewed
• [Journal Article] Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients. Proposal of diagnostic criteria using FGF23 measurement (2008)
  • Author(s): Endo I, et al.
  • Journal Title: Bone 42 Pages: 1235-1239
  • Peer Reviewed
• [Presentation] Molecular mechanisms underlying the phosphate homeostasis. (2011)
  • Author(s): Michigami T.
  • Organizer: The 15^<th> Congress of the International Pediatric Nephrology Association.
  • Place of Presentation: New York, U.S.A.
  • Year and Date: 2011-09-01
• [Presentation] Signal transduction triggered by extracellular inorganic phosphate involves FGF receptor and influences the FGF23 signaling. (2010)
  • Author(s): Yamazaki M, Ozono K, Okada T, Ohata Y, Tachikawa K, Kondou H, Michigami T.
  • Organizer: 14th International Congress of Endocrinology
  • Place of Presentation: 京都
  • Year and Date: 2010-03-29
• [Presentation] Signal transduction triggered by extracellular inorganic phosphate involves FGF receptor and influences the FGF23 signaling. (2010)
  • Author(s): Yamazaki M, et al.
  • Organizer: 第14回国際内分泌会議
  • Place of Presentation: 京都
  • Year and Date: 2010-03-29
• [Presentation] ヒト胎児腎臓由来細胞株HEK293における細胞外無機リン酸シグナル伝達にはIII型Na^+/Pi共輸送担体Pit-1とFGF receptor substrate 2α(FRS2α)が関与する (2008)
  • Author(s): 山崎美和,岡田知子,立川加奈子,大幡泰久,大薗惠一,道上敏美
  • Organizer: 第26回日本骨代謝学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2008-10-30
• [Presentation] Signaling of extracellular inorganic phosphate mediated via sodium-phosphate co-transporters influences FGF23 signaling in renal tubular cells. (2008)
  • Author(s): Yamazaki M, Okada T, Tachikawa K, Ozono K, Michigami T.
  • Organizer: 30th Annual Meeting of the American Society for Bone and Mineral Research.
  • Place of Presentation: Montreal
  • Year and Date: 2008-09-14
• [Presentation] Signaling of extracellular inorganic phosphate mediated via sodium phosphate co-transporters influences FGF23 signaling in renal tubular cells (2008)
  • Author(s): Yamazaki M, et al.
  • Organizer: 第30回アメリカ骨代謝学会
  • Place of Presentation: モントリオール
  • Year and Date: 2008-09-14