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Increases in fibroblastic growth factor 23 (FGF23 or Fgf23) production by osteocytes result in hypophosphatemia and rickets in the  Hyp  mouse homologue of X-linked hypophosphatemia (XLH). Fibroblastic growth factor (FGF) signaling has been implicated in the pathogenesis of  Hyp . Here, we conditionally deleted FGF receptor 1 ( FGFR1  or  Fgfr1 ) in osteocytes of  Hyp  mice to investigate the role of autocrine/paracrine FGFR signaling in regulating FGF23 production by osteocytes. Crossing dentin matrix protein 1 ( Dmp1 )-Cre; Fgfr1   null/+  mice with female  Hyp ; Fgfr1   flox/flox  mice created  Hyp  and  Fgfr1  ( Fgfr1 Dmp1-cKO  )-null mice ( Hyp ; Fgfr1   Dmp1- cKO  ) with a 70% decrease in bone  Fgfr1  transcripts.  Fgfr1 Dmp1-cKO  -null mice exhibited a 50% reduction in  FGF23  expression in bone and 3-fold reduction in serum FGF23 concentrations, as well as reductions in  sclerostin  ( Sost) , phosphate regulating endopeptidase on X chromosome  (PHEX or Phex) , matrix extracellular phosphoglycoprotein ( Mepe ), and  Dmp1  transcripts, but had no demonstrable alterations in phosphate or vitamin D homeostasis or skeletal morphology.  Hyp  mice had hypophosphatemia, reductions in 1,25(OH) 2 D levels, rickets/osteomalacia and elevated FGF2 expression in bone. Compared to  Hyp  mice, compound  Hyp ; Fgfr1   Dmp1 - cKO -null mice had significant improvement in rickets and osteomalacia in association with a decrease in  s erum FGF23 (3607 to 1099 pg/ml), an increase in serum phosphate (6.0 mg/dl to 9.3 mg/dl) and 1,25(OH) 2 D (121±23 to 192±34 pg/ml) levels, but only a 30% reduction in bone  FGF23  mRNA expression. FGF23 promoter activity in osteoblasts was stimulated by FGFR1 activation and inhibited by overexpression of a dominant negative FGFR1(TK−), PLCγ and MAPK inhibitors. FGF2 also stimulated the translation of an FGF23 cDNA transfected into osteoblasts via a FGFR1 and PI3K/Akt-dependent mechanism. Thus, activation of autocrine/paracrine FGF pathways is involved in the pathogenesis of  Hyp  through FGFR1-dependent regulation of FGF23 by both transcriptional and post-transcriptional mechanisms. This may serve to link local bone metabolism with systemic phosphate and vitamin D homeostasis.

Osteocyte-Specific Deletion of Fgfr1 Suppresses FGF23