The
vitamin D hormone,
1,25-dihydroxyvitamin D(3) [
1,25(OH)(2)D(3)], binds with high affinity to the nuclear
vitamin D receptor (VDR), which recruits its
retinoid X receptor (RXR) heterodimeric partner to recognize
vitamin D responsive elements (VDREs) in target genes.
1,25(OH)(2)D(3) is known primarily as a regulator of
calcium, but it also controls
phosphate (re)absorption at the intestine and kidney.
Fibroblast growth factor 23 (FGF23) is a phosphaturic
hormone produced in osteoblasts that, like PTH, lowers serum
phosphate by inhibiting renal reabsorption through Npt2a/Npt2c. Real-time PCR and reporter gene transfection assays were used to probe VDR-mediated transcriptional control by
1,25(OH)(2)D(3). Reporter gene and mammalian two-hybrid transfections, plus competitive receptor binding assays, were used to discover novel VDR
ligands.
1,25(OH)(2)D(3) induces FGF23 78-fold in osteoblasts, and because FGF23 in turn represses
1,25(OH)(2)D(3) synthesis, a reciprocal relationship is established, with FGF23 indirectly curtailing 1,25(OH)(2)D(3)-mediated intestinal absorption and counterbalancing renal reabsorption of
phosphate, thereby reversing
hyperphosphatemia and preventing ectopic calcification. Therefore, a 1,25(OH)(2)D(3)-FGF23 axis regulating
phosphate is comparable in importance to the 1,25(OH)(2)D(3)-PTH axis that regulates
calcium.
1,25(OH)(2)D(3) also elicits regulation of LRP5, Runx2, PHEX, TRPV6, and Npt2c, all anabolic toward bone, and RANKL, which is catabolic. Regulation of mouse RANKL by
1,25(OH)(2)D(3) supports a cloverleaf model, whereby VDR-RXR heterodimers bound to multiple VDREs are juxtapositioned through
chromatin looping to form a supercomplex, potentially allowing simultaneous interactions with multiple co-modulators and chromatin remodeling
enzymes. VDR also selectively binds certain omega3/omega6
polyunsaturated fatty acids (PUFAs) with low affinity, leading to transcriptionally active VDR-RXR complexes. Moreover, the turmeric-derived
polyphenol,
curcumin, activates transcription of a VDRE reporter construct in human
colon cancer cells. Activation of VDR by PUFAs and
curcumin may elicit unique, 1,25(OH)(2)D(3)-independent signaling pathways to orchestrate the bioeffects of these
lipids in intestine, bone, skin/hair follicle, and other VDR-containing tissues.