title: Chronic inhibition of ERK1/2 signaling improves disordered bone and mineral metabolism in hypophosphatemic (Hyp) mice.
abstract: The X-linked hypophosphatemic (Hyp) mouse carries a loss-of-function mutation in the phex gene and is characterized by hypophosphatemia due to renal phosphate (Pi) wasting, inappropriately suppressed 1,25-dihydroxyvitamin D [1,25(OH)₂D] production, and rachitic bone disease. Increased serum fibroblast growth factor-23 concentration is responsible for the disordered metabolism of Pi and 1,25(OH)₂D. In the present study, we tested the hypothesis that chronic inhibition of fibroblast growth factor-23-induced activation of MAPK signaling in Hyp mice can reverse their metabolic derangements and rachitic bone disease. Hyp mice were administered the MAPK inhibitor, PD0325901 orally for 4 wk. PD0325901 induced a 15-fold and 2-fold increase in renal 1α-hydroxylase mRNA and protein abundance, respectively, and thereby higher serum 1,25(OH)₂D concentrations (115 ± 13 vs. 70 ± 16 pg/ml, P < 0.05), compared with values in vehicle-treated Hyp mice. With PD0325901, serum Pi levels were higher (5.1 ± 0.5 vs. 3 ± 0.2 mg/dl, P < 0.05), and the protein abundance of sodium-dependent phosphate cotransporter Npt2a, was greater than in vehicle-treated mice. The rachitic bone disease in Hyp mice is characterized by abundant unmineralized osteoid bone volume, widened epiphyses, and disorganized growth plates. In PD0325901-treated Hyp mice, mineralization of cortical and trabecular bone increased significantly, accompanied by a decrease in unmineralized osteoid volume and thickness, as determined by histomorphometric analysis. The improvement in mineralization in PD0325901-treated Hyp mice was confirmed by microcomputed tomography analysis, which showed an increase in cortical bone volume and thickness. These findings provide evidence that in Hyp mice, chronic MAPK inhibition improves disordered Pi and 1,25(OH)₂D metabolism and bone mineralization.
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, California 94143-0748, USA.
authors.forename: Martin Y H
authors.initials: MY
authors.lastname: Zhang
authors.forename: Daniel
authors.initials: D
authors.lastname: Ranch
authors.forename: Renata C
authors.initials: RC
authors.lastname: Pereira
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Armbrecht
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Portale
authors.forename: Farzana
authors.initials: F
authors.lastname: Perwad
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001847:Bone Diseases / Q000378:metabolism*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors; D017674:Hypophosphatemia / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008903:Minerals / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics; D010710:Phosphates / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D008903:Minerals; D010710:Phosphates; D014807:Vitamin D; D005346:Fibroblast Growth Factors; C097949:1,25-dihydroxyvitamin D; D000089703:Fibroblast Growth Factor-23; C506614:mirdametinib; D004159:Diphenylamine; D020929:Mitogen-Activated Protein Kinase Kinases; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506232:Phex protein, mouse