| 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)
井上 勝 岡山大学, 医学部・歯学部附属病院, 講師 (20253023)
清野 佳紀 岡山大学, 大学院・医歯学総合研究科, 教授 (80028620)
|
|---|
| Budget Amount *help |
¥12,100,000 (Direct Cost: ¥12,100,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2002: ¥8,500,000 (Direct Cost: ¥8,500,000)
|
|---|
| 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
… More
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
|
