[HTML][HTML] Osteocyte-Specific Deletion of Fgfr1 Suppresses FGF23
PloS one, 2014•journals.plos.org
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 …
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 …
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;Fgfr1null/+ mice with female Hyp;Fgfr1flox/flox mice created Hyp and Fgfr1 (Fgfr1Dmp1-cKO)-null mice (Hyp;Fgfr1Dmp1-cKO) with a 70% decrease in bone Fgfr1 transcripts. Fgfr1Dmp1-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)2D levels, rickets/osteomalacia and elevated FGF2 expression in bone. Compared to Hyp mice, compound Hyp;Fgfr1Dmp1-cKO-null mice had significant improvement in rickets and osteomalacia in association with a decrease in serum FGF23 (3607 to 1099 pg/ml), an increase in serum phosphate (6.0 mg/dl to 9.3 mg/dl) and 1,25(OH)2D (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.
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