To elucidate the precise physiological regulation of FGF-23, we characterized the mouse FGF-23 5Ј-flanking region and analyzed its promoter activity. The 5Ј-flanking region of the mouse FGF-23 gene contained a TFIID site (TATA box) and several putative transcription factor binding sites, including MZF1, GATA-1 and c-Ets-1 motifs, but it did not contain the typical sequences of the vitamin D response element. Plasmids encoding 554-bp (pGL/Ϫ0.6), 364-bp (pGL/Ϫ0.4) and 200-bp (pGL/Ϫ0.13) promoter regions containing the TFIID element and ϩ1-bp fragments drove the downstream expression of a luciferase reporter gene in transfection assays. We also found that FGF-23 mRNA was expressed in K-562 erythroleukemia cell lines but not in MC3T3-E1, Raji, or Hep G2 human carcinoma cells. Treatment with 1,25-dihydroxyvitamin D 3 in the presence of high phosphate markedly stimulated pGL/Ϫ0.6 activity, but calcium had no effect. In addition, the plasma FGF-23 levels were affected by the dietary and plasma inorganic phosphate concentrations. Finally, the levels of plasma FGF-23 in vitamin D receptor-null mice were significantly lower than in wild-type mice. The presents study demonstrated that vitamin D and the plasma phosphate level are important regulators of the transcription of the mouse FGF-23 gene. gene regulation; vitamin D receptor; phosphate homeostasis THE HOMEOSTASIS OF PLASMA PHOSPHATE is essential for many biological processes, including skeletal mineralization and energy metabolism. Recent investigations of diseases with abnormal phosphate homeostasis have revealed circulating phosphaturic hormones, collectively called phosphatonin (6, 23). Common clinical features, including hypophosphatemia resulting from renal phosphate wasting and impaired mineralization of bone are shared by X-linked hypophosphatemic rickets (XLH), tumor-induced osteomalacia (TIO), and autosomal-dominant hypophosphatemic rickets (ADHR; see Refs. 28,31,and 32), and the presence of a phosphatonin has been suspected in patients with these diseases because their plasma calcium and parathyroid hormone (PTH) levels are usually normal (8,9).Genetic studies of ADHR and TIO have identified fibroblast growth factor (FGF)-23 as a likely candidate for phosphatonin (28,31). In addition, continuous exposure to recombinant FGF-23 reproduces hypophosphatemic osteomalacia and the inappropriately low plasma levels of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ; see Ref. 28]. Also, a mutant form of FGF-23 (FGF-23R179Q), which is derived from disease-causing missense mutations of ADHR, is resistant to proteolytic processing that normally converts the biologically functional full-length polypeptide into inactive fragments (3, 33). Furthermore, elevated circulatory levels of FGF-23 occur not only in patients with TIO but also in those with XLH (35). These findings indicate that excess FGF-23 activity causes the hypophosphatemia and impaired mineralization of bone that is associated with phosphatonin (6, 21).In a previous study, we demonstrated that the mutant FGF-23 su...

During bone resorption, a large amount of inorganic phosphate (P(i)) is generated within the osteoclast hemivacuole. The mechanisms involved in the disposal of this P(i) are not clear. In the present study, we investigated the efflux of P(i) from osteoclast-like cells. P(i) efflux was activated by acidic conditions in osteoclast-like cells derived by the treatment of RAW264.7 cells with receptor activator of nuclear factor-kappaB ligand. Acid-induced P(i) influx was not observed in renal proximal tubule-like opossum kidney cells, osteoblast-like MC3T3-E1 cells, or untreated RAW264.7 cells. Furthermore, P(i) efflux was stimulated by extracellular P(i) and several P(i) analogs [phosphonoformic acid (PFA), phosphonoacetic acid, arsenate, and pyrophosphate]. P(i) efflux was time dependent, with 50% released into the medium after 10 min. The efflux of P(i) was increased by various inhibitors that block P(i) uptake, and extracellular P(i) did not affect the transport of [(14)C]PFA into the osteoclast-like cells. Preloading of cells with P(i) did not stimulate P(i) efflux by PFA, indicating that the effect of P(i) was not due to transstimulation of P(i) transport. P(i) uptake was also enhanced under acidic conditions. Agents that prevent increases in cytosolic free Ca(2+) concentration, including acetoxymethyl ester of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, 2-aminoethoxydiphenyl borate, and bongkrekic acid, significantly inhibited P(i) uptake in the osteoclast-like cells, suggesting that P(i) uptake is regulated by Ca(2+) signaling in the endoplasmic reticulum and mitochondria of osteoclast-like cells. These results suggest that osteoclast-like cells have a unique P(i) uptake/efflux system and can prevent P(i) accumulation within osteoclast hemivacuoles.

We investigated the effects of defatted-dried chicken skin powder (DCS) containing sphingomyelin (SM) on human facial skin conditions. A placebo-controlled, double-blind 12-week study of DCS (1 g/day ; SM2 mg/day) was conducted on 36 female volunteers who tend to have dry skin. In the DCS group, the moisture of the stratum corneum of cheek tended to increase after 12 weeks. In the subjects whose moisture of cheek was less than 35 arbitrary unit, the DCS group was significantly higher than the placebo group. After 12 weeks, skin elasticity showed significantly increase in the DCS group compared with 0w. These results indicate that the ingestion of DCS improves dry facial skin.

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