title: Dietary phosphate supplement does not rescue skeletal phenotype in a mouse model for craniometaphyseal dysplasia.
abstract: BACKGROUND
  Mutations in the human progressive ankylosis gene (ANKH; Mus musculus ortholog Ank) have been identified as cause for craniometaphyseal dysplasia (CMD), characterized by progressive thickening of craniofacial bones and flared metaphyses of long bones. We previously reported a knock-in (KI) mouse model (AnkKI/KI) for CMD and showed transiently lower serum phosphate (Pi) as well as significantly higher mRNA levels of fibroblast growth factor 23 (Fgf23) in AnkKI/KImice. FGF23 is secreted by bone and acts in kidney to promote Pi wasting which leads to lower serum Pi levels. Here, we examined whether increasing the Pi level can partially rescue the CMD-like skeletal phenotype by feeding Ank+/+and AnkKI/KImice with high Pi (1.7 %) diet from birth for 6 weeks. We studied the Pi metabolism in AnkKI/KImice and CMD patients by examining the Pi regulators FGF23 and parathyroid hormone (PTH).
  
  
  RESULTS
  High Pi diet did not correct CMD-like features, including massive jawbone, increased endosteal and periosteal perimeters and extensive trabeculation of femurs in AnkKI/KImice shown by computed microtomography (μCT). This unexpected negative result is, however, consistent with normal serum/plasma levels of the intact/active form of FGF23 and PTH in AnkKI/KImice and in CMD patients. In addition, FGF23 protein expression was unexpectedly normal in AnkKI/KIfemoral cortical bone as shown by immunohistochemistry despite increased mRNA levels for Fgf23. Renal expression of genes involved in the FGF23 bone-kidney axis, including mFgfr1, mKlotho, mNpt2a, mCyp24a1 and m1αOHase, were comparable between Ank+/+and AnkKI/KImice as shown by quantitative real-time PCR. Different from normal FGF23 and PTH, serum 25-hydroxyvitamin D was significantly lower in AnkKI/KImice and vitamin D insufficiency was found in four out of seven CMD patients.
  
  
  CONCLUSIONS
  Our data suggests that FGF23 signaling and Pi metabolism are not significantly affected in CMD and transiently low Pi level is not a major contributor to CMD.
authors: Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, University of Connecticut Health, Farmington, CT, 06030, USA.
authors: Yaling
authors: Y
authors: Liu
authors: Department of Craniofacial Sciences, School of Dental Medicine, University of Connecticut Health, Farmington, CT, 06030, USA.
authors: Eliane H
authors: EH
authors: Dutra
authors: Department of Reconstructive Sciences, School of Dental Medicine, University of Connecticut Health, Farmington, CT, 06030, USA.
authors: Ernst J
authors: EJ
authors: Reichenberger
authors: Department of Oral Health and Diagnostic Sciences, School of Dental Medicine, University of Connecticut Health, Farmington, CT, 06030, USA. ipchen@uchc.edu.|Department of Oral Health and Diagnostic Sciences, University of Connecticut Health (UConn Health), 263 Farmington Avenue, Farmington, CT, 06030-3705, USA. ipchen@uchc.edu.
authors: I-Ping
authors: IP
authors: Chen
mesh_terms: D000293:Adolescent; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001848:Bone Diseases, Developmental / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology*; D002648:Child; D019465:Craniofacial Abnormalities / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D004032:Diet; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015576:Hyperostosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D006972:Hypertelorism / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009929:Organ Size / Q000187:drug effects; D010281:Parathyroid Hormone / Q000097:blood; D010641:Phenotype; D010710:Phosphates / Q000494:pharmacology / Q000627:therapeutic use*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood; D055114:X-Ray Microtomography
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010281:Parathyroid Hormone; D010710:Phosphates; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C104450:25-hydroxyvitamin D
keywords: ANKH; Craniometaphyseal dysplasia; FGF23; Phosphate diet