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;Fgfr1 null/+ mice with female Hyp;Fgfr1 flox/flox mice created Hyp and Fgfr1 (Fgfr1Dmp1-cKO)-null mice (Hyp;Fgfr1 Dmp1-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;Fgfr1 Dmp1-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.
Highlights
The Fibroblastic growth factor (FGF) family consists of canonical FGFs, intracellular FGFs, and hormone-like FGF gene products (i.e., FGF19, FGF21 and FGF23)
We find an important role of FGFR1 signaling in osteocytes in mediating the increase of FGF23 caused by Phex mutations in Hyp mice, thereby linking alterations autocrine/paracrine functions of FGF/FGFR1 pathways in the bone microenvironment with the secretion of circulating FGF23 that activates FGFRs in distal tissues to coordinate bone mineralization with renal regulation of phosphate and vitamin D metabolism
Consistent with the absence of Dmp1Cre expression in kidney, there were no reduction in Fgfr1 transcripts in the kidney of dentin matrix protein 1 (Dmp1)-Cre;Fgfr1flox/+, but Fgfr1 transcripts were reduced by 50% in Fgfr1Dmp1-cKO-null mice, consistent with the presence of a null Fgfr1 allele (Figure 1D)
Summary
The FGF family consists of canonical FGFs, intracellular FGFs, and hormone-like FGF gene products (i.e., FGF19, FGF21 and FGF23). Canonical or FGFs evolved later to serve autocrine/paracrine functions These secreted FGFs have high heparin affinity, limited diffusion capacity and act locally on cell surface FGF receptors [2]. Circulating FGFs emerged with the capability to diffuse from tissues and target FGF receptor/Klotho complexes at distal sites due to their unique C-terminal domain [3]. FGF23 is a ,32 kDa hormone with an N-terminal FGF-homology domain and a novel 71 amino acid C-terminus [4] that allows it to be released into the circulation and to interact with a-Klotho, a type I membrane, bglycosidase to form a trimeric complex with FGFRs in specific tissues [4,5,6,7,8,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
