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Increased EFG- and PDGFalpha-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis.
Hum Mol Genet 2010; 19(9):1678-89HM

Abstract

Dysregulations of osteoblast function induced by gain-of-function genetic mutations in fibroblast growth factor receptors (FGFRs) cause premature fusion of cranial sutures in syndromic craniosynostosis. The pathogenic signaling mechanisms induced by FGFR genetic mutations in human craniosynostosis remain largely unknown. In this study, we have used microarray analysis to investigate the signaling pathways that are activated by FGFR2 mutations in Apert craniosynostosis. Transcriptomic analysis revealed that EGFR and PDGFRalpha expression is abnormally increased in human Apert calvaria osteoblasts compared with wild-type cells. Quantitative RT-PCR and western blot analyses in Apert osteoblasts and immunohistochemical analysis of Apert sutures confirmed the increased EGFR and PDGFRalpha expression in vitro and in vivo. We demonstrate that pharmacological inhibition of EGFR and PDGFR reduces the pathological upregulation of phenotypic osteoblast genes and in vitro matrix mineralization in Apert osteoblasts. Investigation of the underlying molecular mechanisms revealed that activated FGFR2 enhances EGFR and PDGFRalpha mRNA expression via activation of PKCalpha-dependent AP-1 transcriptional activity. We also show that the increased EGFR protein expression in Apert osteoblasts results in part from a post-transcriptional mechanism involving increased Sprouty2-Cbl interaction, leading to Cbl sequestration and reduced EGFR ubiquitination. These data reveal novel molecular crosstalks between activated FGFR2, EGFR and PDGFRalpha that functionally contribute to the osteoblastic dysfunction in Apert craniosynostosis, which may provide a molecular basis for novel therapeutic approaches in this severe skeletal disorder.

Authors+Show Affiliations

Laboratory of Osteoblast Biology and Pathology, Inserm U606, Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20124286

Citation

Miraoui, Hichem, et al. "Increased EFG- and PDGFalpha-receptor Signaling By Mutant FGF-receptor 2 Contributes to Osteoblast Dysfunction in Apert Craniosynostosis." Human Molecular Genetics, vol. 19, no. 9, 2010, pp. 1678-89.
Miraoui H, Ringe J, Häupl T, et al. Increased EFG- and PDGFalpha-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis. Hum Mol Genet. 2010;19(9):1678-89.
Miraoui, H., Ringe, J., Häupl, T., & Marie, P. J. (2010). Increased EFG- and PDGFalpha-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis. Human Molecular Genetics, 19(9), pp. 1678-89. doi:10.1093/hmg/ddq045.
Miraoui H, et al. Increased EFG- and PDGFalpha-receptor Signaling By Mutant FGF-receptor 2 Contributes to Osteoblast Dysfunction in Apert Craniosynostosis. Hum Mol Genet. 2010 May 1;19(9):1678-89. PubMed PMID: 20124286.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased EFG- and PDGFalpha-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis. AU - Miraoui,Hichem, AU - Ringe,Jochen, AU - Häupl,Thomas, AU - Marie,Pierre J, Y1 - 2010/02/02/ PY - 2010/2/4/entrez PY - 2010/2/4/pubmed PY - 2010/8/26/medline SP - 1678 EP - 89 JF - Human molecular genetics JO - Hum. Mol. Genet. VL - 19 IS - 9 N2 - Dysregulations of osteoblast function induced by gain-of-function genetic mutations in fibroblast growth factor receptors (FGFRs) cause premature fusion of cranial sutures in syndromic craniosynostosis. The pathogenic signaling mechanisms induced by FGFR genetic mutations in human craniosynostosis remain largely unknown. In this study, we have used microarray analysis to investigate the signaling pathways that are activated by FGFR2 mutations in Apert craniosynostosis. Transcriptomic analysis revealed that EGFR and PDGFRalpha expression is abnormally increased in human Apert calvaria osteoblasts compared with wild-type cells. Quantitative RT-PCR and western blot analyses in Apert osteoblasts and immunohistochemical analysis of Apert sutures confirmed the increased EGFR and PDGFRalpha expression in vitro and in vivo. We demonstrate that pharmacological inhibition of EGFR and PDGFR reduces the pathological upregulation of phenotypic osteoblast genes and in vitro matrix mineralization in Apert osteoblasts. Investigation of the underlying molecular mechanisms revealed that activated FGFR2 enhances EGFR and PDGFRalpha mRNA expression via activation of PKCalpha-dependent AP-1 transcriptional activity. We also show that the increased EGFR protein expression in Apert osteoblasts results in part from a post-transcriptional mechanism involving increased Sprouty2-Cbl interaction, leading to Cbl sequestration and reduced EGFR ubiquitination. These data reveal novel molecular crosstalks between activated FGFR2, EGFR and PDGFRalpha that functionally contribute to the osteoblastic dysfunction in Apert craniosynostosis, which may provide a molecular basis for novel therapeutic approaches in this severe skeletal disorder. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/20124286/Increased_EFG__and_PDGFalpha_receptor_signaling_by_mutant_FGF_receptor_2_contributes_to_osteoblast_dysfunction_in_Apert_craniosynostosis_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddq045 DB - PRIME DP - Unbound Medicine ER -