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Isolation of Mesenchymal Stem Cells from Human Alveolar Periosteum and Effects of Vitamin D on Osteogenic Activity of Periosteum-derived Cells
Published on: May 4, 2018
Molecular mechanisms of cadmium-induced fibroblast growth factor 23 upregulation in osteoblast-like cells
Shinsuke Kido1, Marina Fujihara, Kengo Nomura
1Department of Molecular Nutrition, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima 770-8503, Japan.
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.
Insights
Chronic cadmium (Cd) intoxication increases bone-derived Fibroblast Growth Factor 23 (FGF23) by upregulating GalNAc-T3 via aryl hydrocarbon receptor (AhR) activation, contributing to Itai-itai disease pathogenesis.
Area of Science:
- Environmental Toxicology
- Bone Biology
- Renal Physiology
Background:
- Itai-itai disease results from chronic cadmium (Cd) intoxication, primarily targeting renal proximal tubules.
- The precise mechanisms linking Cd-induced renal damage to bone lesions remain unclear.
- Fibroblast Growth Factor 23 (FGF23), a bone-derived factor, regulates phosphate and vitamin D metabolism, but its role in Cd toxicity is not fully understood.
Purpose of the Study:
- To investigate the mechanisms underlying Cd-induced FGF23 production in bone.
- To elucidate the role of GalNAc-T3 and aryl hydrocarbon receptors (AhR) in Cd toxicity.
- To clarify the relationship between Cd exposure, FGF23, and bone pathology.
Main Methods:
- Cd was administered to mice, and plasma FGF23 concentrations and bone FGF23 mRNA expression were analyzed.
- GalNAc-T3 mRNA expression was examined in vivo (Cd-injected mice) and in vitro (cultured osteosarcoma cells and primary osteocytes).
- The involvement of AhR activation, including its phosphorylation and binding to the GalNAc-T3 promoter, was assessed using antagonists and siRNA.
Main Results:
- Cd injection significantly increased plasma FGF23 levels without altering bone FGF23 mRNA expression.
- GalNAc-T3 gene expression was significantly upregulated in the bones of Cd-exposed mice and in cultured bone cells.
- Cd activated AhR, which was essential for GalNAc-T3 gene expression, and Cd-induced FGF23 production was inhibited by AhR antagonism.
Conclusions:
- Cd exposure increases GalNAc-T3 expression in bone, likely through AhR activation and subsequent binding to the GalNAc-T3 promoter.
- This upregulation of GalNAc-T3 may suppress FGF23 proteolytic processing, leading to elevated serum FGF23 concentrations.
- These findings provide novel insights into the pathogenesis of Cd-induced bone lesions and Itai-itai disease.
