Fibroblast growth factor-23 increases mouse PGE₂production in vivo and in vitro

Abstract

Fibroblast growth factor-23 (FGF-23) has been implicated in the renal phosphate wasting in X-linked hypophosphatemia, tumor-induced osteomalacia, and autosomal dominant hypophosphatemic rickets. Recently, we demonstrated that Hyp mice have greater urinary PGE2 levels compared with C57/B6 mice and that indomethacin administration in vivo and in vitro ameliorates the phosphate transport defect in Hyp mice. To determine further whether altered prostaglandin metabolism plays a role in the renal phosphate transport defect in Hyp mice, we incubated renal proximal tubules with arachidonic acid. We find that PGE2 production was higher in Hyp mice than in C57/B6 mice. Incubation of C57/B6 mouse renal proximal tubules with FGF-23R176Q, an active mutant form of FGR23, increased tubular PGE 2 production, an effect that was inhibited by 50 M PD-98059 and 10 M SB-203580, inhibitors of the MAP kinase pathway. C57/B6 mice injected with FGF-23R176Q had a ϳ10-fold increase in PGE 2 excretion 24 h after intraperitoneal injection of FGF-23R176Q compared with vehicle-treated controls. Finally, we show that PGE 2 inhibited both phosphate and volume absorption in mouse proximal convoluted tubules perfused in vitro and reduced brush-border membrane vesicle NaPi-2a protein abundance from renal cortex incubated in vitro with PGE 2. In conclusion, FGF-23 increases urinary and renal tubular PGE 2 production via the MAP kinase pathway and PGE2 inhibits proximal tubule phosphate transport. volume absorption; in vitro microperfusion; NaPi-2a; rickets; prostaglandin E2 TUMOR-INDUCED osteomalacia, X-linked hypophosphatemia, and autosomal dominant hypophosphatemic rickets are characterized by hypophosphatemia, hyperphosphaturia, inappropriately normal 1,25(OH) 2 vitamin D levels for the degree of hypophosphatemia, and defective bone mineralization. Serum fibroblast growth factor-23 (FGF-23) levels are increased in these three disorders. In tumor-induced osteomalacia, a rare paraneoplastic disorder seen in patients with mesenchymal tumors, there is renal phosphate wasting due to increased FGF-23 production (8,9,17,37) and likely the secretion of other phosphaturic peptides previously known as phosphatonins (9). Tumor resection results in a reduction in FGF-23 to normal levels with concomitant correction of the disordered phosphate metabolism (39). X-linked hypophosphatemia is due to a mutation in the PHEX gene (11,15,24,31). The PHEX gene is a phosphate-regulating gene with endopeptidase activity, which is located on the X chromosome. X-linked hypophosphatemia may be due to failure to inactivate normal circulating FGF-23 (7). However, others have found that FGF-23 is not a PHEX substrate (13,20) and that in some way inactive PHEX results in increased production of . Most patients with X-linked hypophosphatemia have inappropriately high levels of 33,40), whereas patients with autosomal dominant hypophosphatemic rickets have a R176Q mutation in FGF-23 that resists proteolytic cleavage resulting in increased FGF-23R176Q serum levels (3,7,30,36,37).W...

Regulation of phosphate transport in proximal tubules

“…Similarly as described for the PTH-induced signaling pathway (see above), the action of FGF-23 was blocked by inhibitors of ERK1/2. In addition, in isolated proximal tubules, FGF-23 was reported to provoke an increase of the production of prostaglandin PGE2 that was also suggested to occur via the MAPK/ERK pathway [111].…”

Prostaglandin E2 increases proximal tubule fluid reabsorption, and modulates cultured proximal tubule cell responses via EP1 and EP4 receptors

“…PGE 2 also reduces phosphate transport in mouse proximal convoluted tubules. 7 Though very little is known about PT salt and water transport in response to PGE 2 , a recent study by Herman et al 8 describes a mechanism involving both protein kinase C and cAMP, by which PGE 2 regulates Na + -K + -ATPase in primary cultures of rabbit renal PT cells. PGE 2 can also mediate the responses of other hormonal systems on PT sodium transport function.…”

Role of prostaglandins in the pathogenesis of X-linked hypophosphatemia

“…3) [66]. Furthermore, proximal tubules incubated in vitro with arachidonic acid showed that Hyp mice had greater rates of PGE 2 production than control mice [67]. Injection of FGF-23 into control mice resulted in an increase in PGE 2 excretion, and incubation of proximal tubules with FGF-23 increased the rate of PGE 2 production to levels comparable to those seen in Hyp mice (Fig.…”