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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.

2008 MAY 30 - (NewsRx.com) -- "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," scientists in the United States report.

"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 omega 3/omega 6 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," wrote P.W. Jurutka and colleagues, Arizona State University.

The researchers concluded: "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."

Jurutka and colleagues published their study in the Journal of Bone and Mineral Research (Vitamin D receptor: Key roles in bone mineral pathophysiology, molecular mechanism of action, and novel nutritional Ligands. Journal of Bone and Mineral Research, 2007;22(Suppl. 2):V2-V10).

For additional information, contact P.W. Jurutka, Arizona State University, Dept. of Integrated Nat Science, Glendale, AZ, USA.

The publisher's contact information for the Journal of Bone and Mineral Research is: American Society Bone & Mineral Research, 2025 M St., N W, Ste. 800, Washington, DC 20036-3309, USA.

Keywords: United States, Glendale, Bone Research, Biotechnology, Bone, Gastroenterology, Gene Therapy, Genetics, Genomics, Hormones, Kidney, Nephrology, Physiology, Reporter Gene, Arizona State University.

This article was prepared by Genomics & Genetics Weekly editors from staff and other reports. Copyright 2008, Genomics & Genetics Weekly via NewsRx.com.