| RRC ID |
44958
|
| Author |
Kido S, Fujihara M, Nomura K, Sasaki S, Mukai R, Ohnishi R, Kaneko I, Segawa H, Tatsumi S, Izumi H, Kohno K, Miyamoto K.
|
| Title |
Molecular mechanisms of cadmium-induced fibroblast growth factor 23 upregulation in osteoblast-like cells.
|
| Journal |
Toxicol Sci
|
| Abstract |
Itai-itai disease is thought to be the result of chronic cadmium (Cd) intoxication. Renal proximal tubules are a major target of Cd toxicity. The whole mechanism of the adverse effects of Cd remains unresolved, especially how renal damage is related to the development of bone lesions. Fibroblast growth factor 23 (FGF23) is a bone-derived phosphaturic factor that regulates vitamin D and inorganic phosphate metabolism in the kidney. To clarify the role of FGF23 on Cd toxicity, we investigated the mechanisms of Cd-induced FGF23 production in the bone. Cd injection into mice significantly increased plasma FGF23 concentrations, but did not change FGF23 mRNA expression in bone. GalNAc-T3 is involved in secreting intact FGF23. To determine potential roles of GalNAc-T3 in Cd-induced FGF23 production, we examined the effect of Cd on GalNAc-T3 mRNA expression in vivo and in vitro. GalNAc-T3 gene expression was significantly increased in the bones of Cd-injected mice. Cd also enhanced the expression of GalNAc-T3 in cultured osteosarcoma UMR106 cells and primary osteocytes. Cd activated aryl hydrocarbon receptors (AhR) and AhR were required for GalNAc-T3 gene expression induced by Cd. In addition, Cd-dependent FGF23 production was completely inhibited by an AhR antagonist. AhR siRNA markedly suppressed the stimulation of transcriptional activity by Cd. Furthermore, Cd induced AhR activation via phosphorylation of Ser-68 by p38 kinase in the nuclear export signal of AhR. Thus, Cd stimulated GalNAc-T3 gene transcription via enhanced AhR binding to the GalNAc-T3 promoter. These findings suggest that the Cd-induced increase in GalNAc-T3 suppresses proteolytic processing of FGF23 and increases serum FGF23 concentrations.
|
| Volume |
139(2)
|
| Pages |
301-16
|
| Published |
2014-6-1
|
| DOI |
10.1093/toxsci/kfu043
|
| PII |
kfu043
|
| PMID |
24614234
|
| MeSH |
Animals
Cadmium Chloride / toxicity*
Cell Culture Techniques
Cell Line, Tumor
Female
Femur / drug effects*
Femur / metabolism
Fibroblast Growth Factor-23
Fibroblast Growth Factors / blood
Fibroblast Growth Factors / genetics*
Gene Expression / drug effects
Mice, Inbred C57BL
Mice, Inbred ICR
N-Acetylgalactosaminyltransferases / genetics*
Osteoblasts / drug effects*
Osteoblasts / metabolism
Osteocytes / drug effects*
Osteocytes / metabolism
Phosphorylation
Receptors, Aryl Hydrocarbon / metabolism
Up-Regulation
p38 Mitogen-Activated Protein Kinases / metabolism
|
| IF |
3.703
|
| Times Cited |
9
|
|
WOS Category
|
TOXICOLOGY
|
| Resource |
| Human and Animal Cells |
293(RCB1637) |
