In Vitro Analysis of FGF-23 Induced Gene Expression Public
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Fibroblast growth factor 23 (FGF-23) has recently been shown to be involved in phosphate regulation and bone mineralization. This study evaluated the effect of FGF-23 on three human cell lines (Caco-2, HK-2, SaOS-2) representing three different sites of phosphate regulation (small intestine, kidney proximal tubules, and bone, respectively). FGF-23 induced gene expression was studied using Clontech human Atlas glass microarrays containing various assortments of genes and by a custom designed oligo microarray containing specific genes selected for their biological relevance to FGF-23's potential function. FGF-23 induced differential gene expression in all three cell types, suggesting that FGF-23 may be capable of acting on these three primary sites of phosphate regulation. Human small intestine-like endothelial cell line, Caco-2, showed upregulation of several genes including parathyroid hormone receptors 1 and 2. FGF-23 inhibited the expression of water channel transporters aquaporin 5 and 6 in human osteoblast-like SaOS-2 cells while upregulating aquaporin expression in HK-2 cells. Somatostatin receptors 1-4 were identified to be upregulated in the human kidney, HK-2 cell line. Mucin 2, a gene that is linked to abnormal cellular growth, was consistently induced by FGF-23 in all three cell lines. Families of aquaporins, somatostatins, parathyroid hormones, and other identified differentially expressed genes are involved in different signaling pathways that are associated with phosphate and calcium regulation. Selected candidates were analyzed further by real-time RT-PCR. These data support FGF-23 induced regulation of aquaporin 5 mRNA in HK-2 cells and 1-alpha-hydroxylase mRNA in Caco cells. FGF-23 induced changes in mRNA analysis of four additional genes was less than two-fold in triplicate analysis of selected samples. Taken together, these results suggest that each cell type may have responded to FGF-23, but additional validation of the array data set will be required to identify those genes specifically regulated by FGF-23. Further refinement of this data set will undoubtedly uncover additional functions of FGF-23 and may provide valuable insight into designing therapeutic approaches for phosphate specific disorders.
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