Novel regulators of Fgf23 expression and mineralization in Hyp bone

Shiguang Liu, Wen Tang, Jianwen Fang, Jinyu Ren, Hua Li, Zhousheng Xiao, Leigh Quarles

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

We used gene array analysis of cortical bone to identify Phex-dependent gene transcripts associated with abnormal Fgf23 production and mineralization in Hyp mice. We found evidence that elevation of Fgf23 expression in osteocytes is associated with increments in Fgf1, Fgf7, and Egr2 and decrements in Sost, an inhibitor in the Wnt-signaling pathway, were observed in Hyp bone. β-Catenin levels were increased in Hyp cortical bone, and TOPflash luciferase reporter assay showed increased transcriptional activity in Hyp-derived osteoblasts, consistent with Wnt activation. Moreover, activation of Fgf and Wnt-signaling stimulated Fgf23 promoter activity in osteoblasts. We also observed reductions in Bmp1, a metalloproteinase that metabolizes the extracellular matrix protein Dmp1. Alterations were also found in enzymes regulating the posttranslational processing and stability of Fgf23, including decrements in the glycosyltransferase Galnt3 and the proprotein convertase Pcsk5. In addition, we found that the Pcsk5 and the glycosyltransferase Galnt3 were decreased in Hyp bone, suggesting that reduced posttranslational processing of FGF23 may also contribute to increased Fgf23 levels in Hyp mice. With regard to mineralization, we identified additional candidates to explain the intrinsic mineralization defect in Hyp osteoblasts, including increases in the mineralization inhibitors Mgp and Thbs4, as well as increases in local pH-altering factors, carbonic anhydrase 12 (Car12) and 3 (Car3) and the sodium-dependent citrate transporter (Slc13a5). These studies demonstrate the complexity of gene expression alterations in bone that accompanies inactivating Phex mutations and identify novel pathways that may coordinate Fgf23 expression and mineralization of extracellular matrix in Hyp bone.

Original languageEnglish (US)
Pages (from-to)1505-1518
Number of pages14
JournalMolecular Endocrinology
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2009
Externally publishedYes

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Osteoblasts
Bone and Bones
Glycosyltransferases
Proprotein Convertases
Osteocytes
Catenins
Wnt Signaling Pathway
Extracellular Matrix Proteins
Metalloproteases
Luciferases
Genes
Extracellular Matrix
Gene Expression
Mutation
Enzymes
Cortical Bone

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

Cite this

Novel regulators of Fgf23 expression and mineralization in Hyp bone. / Liu, Shiguang; Tang, Wen; Fang, Jianwen; Ren, Jinyu; Li, Hua; Xiao, Zhousheng; Quarles, Leigh.

In: Molecular Endocrinology, Vol. 23, No. 9, 01.09.2009, p. 1505-1518.

Research output: Contribution to journalArticle

Liu, Shiguang ; Tang, Wen ; Fang, Jianwen ; Ren, Jinyu ; Li, Hua ; Xiao, Zhousheng ; Quarles, Leigh. / Novel regulators of Fgf23 expression and mineralization in Hyp bone. In: Molecular Endocrinology. 2009 ; Vol. 23, No. 9. pp. 1505-1518.
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