title: Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX.
abstract: Inactivating mutations of Phex cause X-linked hypophosphatemia (XLH) by increasing levels of a circulating phosphaturic factor. FGF23 is a candidate for this phosphaturic factor. Elevated serum FGF23 levels correlate with the degree of hypophosphatemia in XLH, suggesting that loss of Phex function in this disorder results in either diminished degradation and/or increased biosynthesis of FGF23. To establish the mechanisms whereby Phex regulates FGF23, we assessed Phex-dependent hydrolysis of recombinant FGF23 in vitro and measured fgf23 message levels in the Hyp mouse homologue of XLH. In COS-7 cells, overexpression of FGF23 resulted in its degradation into N- and C-terminal fragments by an endogenous decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone-sensitive furin-type convertase. Phex-dependent hydrolysis of full-length FGF23 or its N- and C-terminal fragments could not be demonstrated in the presence or absence of decanoyl-Arg-Val-Lys-Arg-chloromethyl ketone in COS-7 cells expressing Phex and FGF23. In a reticulolysate system, apparent cleavage of FGF23 occurred with wild-type Phex, the inactive Phex-3'M mutant, and vector controls, indicating nonspecific metabolism of FGF23 by contaminating enzymes. These findings suggest that FGF23 is not a direct Phex substrate. In contrast, by real-time reverse transcriptase PCR, the levels of fgf23 transcripts were highest in bone, the predominant site of Phex expression. In addition, Hyp mice displayed a bone-restricted increase in fgf23 transcripts in association with inactivating Phex mutations. Increased expression of fgf23 was also observed in Hyp-derived osteoblasts in culture. These findings suggest that Phex, possibly through the actions of unidentified Phex substrates or other downstream effectors, regulates fgf23 expression as part of a potential hormonal axis between bone and kidney that controls systemic phosphate homeostasis and mineralization.
authors.affiliation: Department of Medicine, Center for Bone and Mineral Disorders, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Shiguang
authors.initials: S
authors.lastname: Liu
authors.forename: Rong
authors.initials: R
authors.lastname: Guo
authors.forename: Leigh G
authors.initials: LG
authors.lastname: Simpson
authors.forename: Zhou-Sheng
authors.initials: ZS
authors.lastname: Xiao
authors.forename: Charles E
authors.initials: CE
authors.lastname: Burnham
authors.forename: L Darryl
authors.initials: LD
authors.lastname: Quarles
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D019556:COS Cells; D016326:Extracellular Matrix Proteins; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D017674:Hypophosphatemia / Q000235:genetics*; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D010280:Parathyroid Glands / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics; D011506:Proteins / Q000502:physiology*; D011817:Rabbits; D014960:X Chromosome
chemical_list: D016326:Extracellular Matrix Proteins; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D006023:Glycoproteins; C486579:MEPE protein, human; D010750:Phosphoproteins; D011506:Proteins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human; C506232:Phex protein, mouse