2004 Fiscal Year Final Research Report Summary
Research on the function of the responsible genes for hypophosphatemic vitamin D resistant rickets and their pathogenetic mechanisms.
| Project/Area Number |
14370337
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Okayama University |
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Principal Investigator |
TANAKA Hiroyuki Okayama University, Graduate School of Medicine and Dentistry, Associate Professor, 大学院・歯学総合研究科, 助教授 (80231413)
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| Co-Investigator(Kenkyū-buntansha) |
NINOMIYA Shinsuke Okayama University, Hospital, Lecture, 医学部・歯学部附属病院, 講師 (10325110)
YAMANAKA Yoshitaka Okayama University, Hospital, Assistant, 医学部・歯学部附属病院, 助手 (60346442)
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| Project Period (FY) |
2002 – 2004
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| Keywords | Hyp / XLH / FGF23 / McCune-Albright Syndrome / GSα / PTH |
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| Research Abstract |
To clarify the pathogenetic mechanism of X-linked hypophosphatemic rickets and to clarify the regulatory mechanism of serum phosphorus concentration, this project was designed. However, at the start of the project, we got a breakthrough, identification of fibroblast growth factor 23(FGF23). FGF23 was identified in tumor induced osteomalacia. The mutations in FGF23 gene is responsible for the other type of hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets (ADHR), which shows similar symptoms to XLH. Moreover, we and the others showed increased serum levels of FGF23 in XLH. These findings led us to explore the regulatory mechanisms of FGF23 under several pathological conditions. We measured serum FGF23 concentrations in various hypophosphatemic conditions, such as XLH, McCune-Albright syndrome, renal Fanconi syndrome. In McCune-Albright syndrome, hypophosphatemia consistently accompanied with increased serum levels of FGF23. Therefore, we studied the mechanism by whic
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h the constitutive active Gs protein induces FGF23 production. To this aid, we have established in vitro experimental system by use ST2 cells, which stably expressed FGF23 mRNA. We also cloned 5' promoter region of FGF23 gene. By using this system, we demonstrated that PTH induced activation of Gs also increased steady state mRNA expression of FGF23 and increased FGF23 protein. As this reaction needed over 12 hours, it seemed to be posttranscriptional events. Luciferase assay experiment using 2kb promoter also suggested that the regulatory mechanism is not transcriptional.. We also performed in vivo experiment using phosphate restriction in wild type mice. The results suggested that hypophosphatemia itself is inhibitory factor for the production of FGF23.
We also analyzed the regulatory mechanism of active vitamin D by the in vitro system. The results suggested that 1,25dihydroxyvitamin D3 positively regulates mRNA expression transcriptionally and that a new vitamin D analog, ED-71, may have low potential for the induction of FGF23. This may be a reason why ED-71 is more potent in the treatment of Hyp mice bone lesion than 1,25dihydroxyvitamin D3. Less
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Research Products
(6 results)
