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Fibroblast growth factor-23 (FGF-23) is critical to the pathogenesis of a distinct group of renal phosphate wasting disorders: tumor-induced osteomalacia, X-linked hypophosphatemia, and autosomal dominant and autosomal recessive hypophosphatemic rickets. Excess circulating FGF-23 is responsible for their major phenotypic features which include hypophosphatemia due to renal phosphate wasting and inappropriately low serum 1,25[(OH).sub.2]D concentrations. To characterize the effects of FGF-23 on renal sodium-phosphate (Na/[P.sub.i]) cotransport and vitamin D metabolism, we administered FGF-23(R176Q) to normal mice. A single injection (0.33 [micro]g/g body wt) induced significant hypophosphatemia, 20 and 29% decreases (P < 0.001) in brush-border membrane (BBM) Na/[P.sub.i] cotransport at 5 and 17 h after injection, respectively, and comparable decreases in the abundance of type IIa Na/[P.sub.i] cotransporter protein in BBM. Multiple injections (6, 12, and 24 [micro]g/day for 4 days) induced dose-dependent decreases (38, 63, and 75%, respectively) in renal abundance of 1[alpha]-hydroxylase mRNA (P < 0.05). To determine whether FGF-23(R176Q) exerts a direct action on 1[alpha]-hydroxylase gene expression, we examined its effects in cultured human (HKC-8) and mouse (MCT) renal proximal tubule cells. FGF-23(R176Q) (1 to 10 ng/ml) induced a dose-dependent decrease in 1[alpha]-hydroxylase mRNA with a maximum suppression of 37% (P < 0.05). Suppression was detectable after 6 h of exposure and maximal after 21 h. In MCT cells, FGF-23(R176Q) suppressed 1[alpha]-hydroxylase mRNA and activated the ERK1/2 signaling pathway. The MAPK inhibitor PD98059 effectively abolished FGF-23-induced suppression of 1[alpha]-hydroxylase mRNA by blocking signal transduction via ERK1/2. These novel findings provide evidence that FGF-23 directly regulates renal l[alpha]-hydroxylase gene expression via activation of the ERK1/2 signaling pathway. bone and mineral homeostasis; hypophosphatemic syndromes

Bladder hypertrophy is a general consequence of bladder outlet obstruction (BOO) and a typical phenomenon observed in clinical urologic diseases such as benign prostatic hyperplasia and neurogenic bladder. It is characterized by smooth muscle hyperplasia, altered extracellular matrix composition, and increased contractile function. Various growth factors are likely involved in hypertrophic pathophysiology, but their functions remain unknown. In this report, the role of basic fibroblast growth factor (bFGF) was investigated using a rat bladder smooth muscle cell (BSMC) culture system and an original animal model, in which bFGF was released from a gelatin hydrogel directly onto rat bladders, bFGF treatment promoted BSMC proliferation both in vitro and in vivo. In vitro, bFGF downregulated the expression of type I collagen, but upregulated type III collagen. ERK1/2, but not p38MAPK, was activated by bFGF, whereas inhibition of ERK1/2 by PD98059 reversed bFGF-induced BSMC proliferation, type I collagen downregulation, and type III collagen upregulation. In the in vivo release model, bFGF upregulated type III collagen and increased the contractile force of treated bladders. In parallel with these findings, hypertrophied rat bladders created by urethral constriction showed increased urothelial bFGF expression, BSMC proliferation, and increased type III collagen expression compared with sham-operated rats. These data suggest that bFGF from the urothelium could act as a paracrine signal that stimulates the proliferation and matrix production of BSMC, thereby contributing to the hypertrophic remodeling of the smooth muscle layer. bFGF; bladder smooth muscle cell; type I collagen; type III collagen; ERK

The effects of fibroblast growth factor 10 on colonic epithelium development, using hypomorphic mice studies, are presented.

Regulation of heart valve progenitor cell diversification by fibroblast growth factor 4 and bone morphogenetic protein 2 is analyzed.

Immunofluorescence in the attachment and outgrowth stages of mouse embryo development in vitro and in utero was employed in the study of cell surface expression of heparan sulfate proteoglycan (HSPG), perlecan, basic fibroblast growth factor binding forms of heparan sulfate and laminin. HSPG and laminin were found to be expressed on the outside surface of the trophectoderm in the attachment phase of implantation in vivo. The HSPG expression corresponded with the attachment ability of the embryos in vitro.

Results show that fibroblast growth factor signaling during mouse gastrulation is promoted by proteoglycans. Data indicate that Izme phenotype cells produce UDP-glucose dehydrogenase which mediate the synthesis of the GAG side chains of proteoglycans and in Izme mutants Fgf signaling is blocked for lack of proteoglycans.