Nuclear isoforms of fibroblast growth factor 2 are novel inducers of hypophosphatemia via modulation of FGF23 and KLOTHO.
FGF2 transgenic mice were developed in which type I collagen regulatory sequences drive the nuclear high molecular weight FGF2 isoforms in osteoblasts (TgHMW). The phenotype of TgHMW mice included dwarfism, decreased bone mineral density (BMD), osteomalacia, and decreased serum phosphate (P(i)). When TgHMW mice were fed a high P(i) diet, BMD was increased, and dwarfism was partially reversed. The TgHMW phenotype was similar to mice overexpressing FGF23. Serum FGF23 was increased in TgHMW mice. Fgf23 mRNA in bones and fibroblast growth factor receptors 1c and 3c and Klotho mRNAs in kidneys were increased in TgHMW mice, whereas the renal Na(+)/P(i) co-transporter Npt2a mRNA was decreased. Immunohistochemistry and Western blot analyses of TgHMW kidneys showed increased KLOTHO and decreased NPT2a protein. The results suggest that overexpression of HMW FGF2 increases FGF23/FGFR/KLOTHO signaling to down-regulate NPT2a, causing P(i) wasting, osteomalacia, and decreased BMD. We assessed whether HMW FGF2 expression was altered in the Hyp mouse, a mouse homolog of the human disease X-linked hypophosphatemic rickets/osteomalacia. Fgf2 mRNA was increased in bones, and Western blots showed increased FGF2 protein in nuclear fractions from osteoblasts of Hyp mice. In addition, immunohistochemistry demonstrated co-localization of FGF23 and HMW FGF2 protein in osteoblasts and osteocytes from Hyp mice. This study reveals a novel mechanism of regulation of the FGF23-P(i) homeostatic axis.
Xiao
Liping
L
Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
Naganawa
Takahiro
T
Lorenzo
Joseph
J
Carpenter
Thomas O
TO
Coffin
J Douglas
JD
Hurley
Marja M
MM
D015502:Absorptiometry, Photon; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D017674:Hypophosphatemia / Q000378:metabolism* / Q000503:physiopathology; D007536:Isomerism; D007668:Kidney / Q000502:physiology; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008970:Molecular Weight; D010006:Osteoblasts / Q000502:physiology; D010018:Osteomalacia / Q000378:metabolism* / Q000503:physiopathology; D010641:Phenotype; D010710:Phosphates / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D012886:Skull / Q000000981:diagnostic imaging / Q000473:pathology; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000378:metabolism; D055114:X-Ray Microtomography
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; C493555:Slc34a1 protein, mouse; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins