Molecular mechanisms of cadmium-induced fibroblast growth factor 23 upregulation in osteoblast-like cells.

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.

• Authors: Shinsuke Kido, Marina Fujihara, Kengo Nomura, Shohei Sasaki, Rie Mukai, Ritsuko Ohnishi, Ichiro Kaneko, Hiroko Segawa, Sawako Tatsumi, Hiroto Izumi, Kimitoshi Kohno, Ken-ichi Miyamoto
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 139 Issue 2 Pg. 301-16 (Jun 2014) ISSN: 1096-0929 [Electronic] United States
• PMID: 24614234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fgf23 protein, mouse
• Receptors, Aryl Hydrocarbon
• Fibroblast Growth Factors
• Fibroblast Growth Factor-23
• N-Acetylgalactosaminyltransferases
• p38 Mitogen-Activated Protein Kinases
• Cadmium Chloride

Topics

• Animals
• Cadmium Chloride (toxicity)
• Cell Culture Techniques
• Cell Line, Tumor
• Female
• Femur (drug effects, metabolism)
• Fibroblast Growth Factor-23
• Fibroblast Growth Factors (blood, genetics)
• Gene Expression (drug effects)
• Mice, Inbred C57BL
• Mice, Inbred ICR
• N-Acetylgalactosaminyltransferases (genetics)
• Osteoblasts (drug effects, metabolism)
• Osteocytes (drug effects, metabolism)
• Phosphorylation
• Receptors, Aryl Hydrocarbon (metabolism)
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases (metabolism)
• Polypeptide N-acetylgalactosaminyltransferase