Osteocyte-specific deletion of Fgfr1 suppresses FGF23

Zhousheng Xiao, Jinsong Huang, Li Cao, Yingjuan Liang, Xiaobin Han, Leigh Quarles

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Abstract

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.

Original languageEnglish (US)
Article numbere104154
JournalPLoS ONE
Volume9
Issue number8
DOIs
StatePublished - Aug 4 2014

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Osteocytes
Bone
Phosphates
mice
Intercellular Signaling Peptides and Proteins
Osteoblasts
rickets
Fibroblast Growth Factor 2
Rickets
growth factors
Vitamin D
Bone and Bones
bones
osteomalacia
phosphates
Chemical activation
Hypophosphatemia
Osteomalacia
osteoblasts
Endopeptidases

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Osteocyte-specific deletion of Fgfr1 suppresses FGF23. / Xiao, Zhousheng; Huang, Jinsong; Cao, Li; Liang, Yingjuan; Han, Xiaobin; Quarles, Leigh.

In: PLoS ONE, Vol. 9, No. 8, e104154, 04.08.2014.

Research output: Contribution to journalArticle

Xiao, Zhousheng ; Huang, Jinsong ; Cao, Li ; Liang, Yingjuan ; Han, Xiaobin ; Quarles, Leigh. / Osteocyte-specific deletion of Fgfr1 suppresses FGF23. In: PLoS ONE. 2014 ; Vol. 9, No. 8.
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