title: Osteocyte-specific deletion of Fgfr1 suppresses FGF23.
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.
authors.affiliation: University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Zhousheng
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Huang
authors.affiliation: University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.affiliation: University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Yingjuan
authors.initials: Y
authors.lastname: Liang
authors.affiliation: University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Han
authors.affiliation: University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors.forename: Leigh Darryl
authors.initials: LD
authors.lastname: Quarles
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D017674:Hypophosphatemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010011:Osteocytes / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D014807:Vitamin D / Q000378:metabolism
chemical_list: C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D012333:RNA, Messenger; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1
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