Skeletal FGFR1 signaling is necessary for regulation of serum phosphate level by FGF23 and normal life span.

Fibroblast growth factor (FGF) 23 produced by the bone is the principal hormone to regulate serum phosphate level. Serum FGF23 needs to be tightly regulated to maintain serum phosphate in a narrow range. Thus, we hypothesized that the bone has some phosphate-sensing mechanism to regulate the production of FGF23. Previously we showed that extracellular phosphate induces the phosphorylation of FGF receptor 1 (FGFR1) and FGFR1 signaling regulates the expression of , whose product works to increase FGF23 production . In this study, we show the significance of FGFR1 in the regulated FGF23 production and serum phosphate level . We generated late-osteoblast/osteocyte-specific -knockout mice ( ) by crossing the and the floxed mouse lines. We evaluated serum phosphate and FGF23 levels, the expression of in the bone, the body weight and life span. A selective ablation of aborted the increase of serum active full-length FGF23 and the enhanced expression of in the bone by a high phosphate diet. These mice showed more pronounced hyperphosphatemia compared with control mice. In addition, these mice fed with a control diet showed body weight loss after 23 weeks of age and shorter life span. These results reveal a novel significance of FGFR1 signaling in the phosphate metabolism and normal life span.