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

细胞外磷酸盐反应机制及影响 FGF23 敏感性的因素

• 批准号: 20590986
• 负责人: MICHIGAMI Toshimi
• 金额: $ 2.91万
• 依托单位: Research Institute, Osaka Medical Center for Maternal and Child Health
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20590986/
• 关键词: 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

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.

磷是参与各种生物过程的关键元素，生物体拥有其稳态系统。然而，检测磷酸盐过量或不足的机制仍不清楚。在这项研究中，我们检查了肾源性细胞系对细胞外磷酸盐的反应性，发现细胞外磷酸盐的增加诱导了 Raf/MEK/ERK 通路的激活，从而导致基因表达的改变。此外，我们发现 III 型钠/磷酸盐协同转运蛋白 PiT-1 以及 FGF 受体参与细胞对细胞外磷酸盐增加的反应。由细胞外磷酸盐增加触发的信号传导与 FGF23 信号传导具有相同的下游级联，表明细胞外磷酸盐本身可能会影响对 FGF23 的敏感性。在血清磷酸盐水平异常的情况下，例如慢性肾病，肾小管对 FGF23 的反应可能会改变。

项目成果

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

• DOI: 10.1016/j.bone.2010.08.006
• 发表时间: 2010-11-01
• 期刊: BONE
• 影响因子: 4.1
• 作者: Kimata, Masaaki;Michigami, Toshimi;Ozono, Keiichi
• 通讯作者: Ozono, Keiichi

Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients - Proposal of diagnostic criteria using FGF23 measurement

• DOI: 10.1016/j.bone.2008.02.014
• 发表时间: 2008-06-01
• 期刊: BONE
• 影响因子: 4.1
• 作者: Endo, Itsuro;Fukumoto, Seiji;Matsumoto, Toshio
• 通讯作者: Matsumoto, Toshio

An Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd.

Lrp6 亚形突变通过小鼠骨吸收影响骨量，并损害与 Mesd 的相互作用。

• 发表时间: 2008
• 期刊: J Bone Miner Res 23
• 作者: Kubota T;Michigami T;Sakaguchi N;Kokubu C;Suzuki A;Namba N;Sakai N;Nakajima S;Imai K;Ozono K.
• 通讯作者: Ozono K.

Clinical characteristics of perinatal lethal hypophosphatasia: a report of 6 cases.

• DOI: 10.1297/cpe.19.7
• 发表时间: 2010-01
• 期刊: Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology
• 作者: 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
• 通讯作者: Kobayashi M

Severe arterial hypertension: a possible complication of McCune-Albright syndrome

严重动脉高血压：麦库尼-奥尔布赖特综合征的可能并发症

• 发表时间: 2009
• 期刊: Eur J Pediatr 168
• 作者: Ohata Y;Yamamoto T;Mori I;Kikuchi T;Michigami T;Imanishi Y;Satomura K;Ida S;Ozono K
• 通讯作者: Ozono K