1α,25-Dihydroxyvitamin D₃upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport

Abstract

Fibroblast growth factor (FGF)23 is a phosphaturic hormone that decreases circulating 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and elicits hypophosphatemia, both of which contribute to rickets/osteomalacia. It has been shown recently that serum FGF23 increases after treatment with renal 1,25(OH)(2)D(3) hormone, suggesting that 1,25(OH)(2)D(3) negatively feedback controls its levels by inducing FGF23. To establish the tissue of origin and the molecular mechanism by which 1,25(OH)(2)D(3) increases circulating FGF23, we administered 1,25(OH)(2)D(3) to C57BL/6 mice. Within 24 h, these mice displayed a dramatic elevation in serum immunoreactive FGF23, and the expression of FGF23 mRNA in bone was significantly upregulated by 1,25(OH)(2)D(3), but there was no effect in several other tissues. Furthermore, we treated rat UMR-106 osteoblast-like cells with 1,25(OH)(2)D(3), and real-time PCR analysis revealed a dose- and time-dependent stimulation of FGF23 mRNA concentrations. The maximum increase in FGF23 mRNA was 1,024-fold at 10(-7) M 1,25(OH)(2)D(3) after 24-h treatment, but statistically significant differences were observed as early as 4 h after 1,25(OH)(2)D(3) treatment. In addition, using cotreatment with actinomycin D or cycloheximide, we observed that 1,25(OH)(2)D(3) regulation of FGF23 gene expression occurs at the transcriptional level, likely via the nuclear vitamin D receptor, and is dependent on synthesis of an intermediary transfactor. These results indicate that bone is a major site of FGF23 expression and source of circulating FGF23 after 1,25(OH)(2)D(3) administration or physiological upregulation. Our data also establish FGF23 induction by 1,25(OH)(2)D(3) in osteoblasts as a feedback loop between these two hormones that completes a kidney-intestine-bone axis that mediates phosphate homeostasis.

Functional heterogeneity of osteocytes in FGF23 production: the possible involvement of DMP1 as a direct negative regulator

“…[40][41][42][43] Therefore, UMR-106 cells are thought to possess surrogate characteristics of the osteoblast/osteocyte lineage. The cells were treated with 10, 50 and 100 ng ml À 1 recombinant DMP1 for 24 h. As shown in Figure 3a, DMP1 significantly reduced the gene expression of fgf23.…”

Elsie Widdowson Lecture 2006 Mining the depths: metabolic insights into mineral nutrition

“…The wide-ranging activity of klotho raises the possibility that regulation of Ca and phosphate metabolism is an Urinary P ↑ Urinary Ca ↓ essential feature of many systems of the body, not just those connected with the skeleton. Further information on this area of discussion is available (1,20,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48) .…”

Changes in bone metabolic parameters following oral calcium supplementation in an adult patient with vitamin D-dependent rickets type 2A

“…3). Considering the fact that VDR-null mice also displayed undetectable FGF23 levels [32,33], and 1,25(OH) 2 D stimulats FGF23 expression [34][35][36], the VDR-vitamin D system definitively plays an important role in FGF23 regulation. It has been shown that FGF23-null mice display hyperphosphatemia, hypercalcemia, elevated serum 1,25(OH) 2 D, and vascular calcification of the kidneys [37].…”