Increased EFG- and PDGFalpha-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis

Human Molecular Genetics
Hichem MiraouiPierre J Marie

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 ...Continue Reading

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Citations

Aug 9, 2012·Child's Nervous System : ChNS : Official Journal of the International Society for Pediatric Neurosurgery·S-G Gong
Jun 20, 2012·Current Osteoporosis Reports·Pierre J Marie
Jul 20, 2011·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Ammad Ahmad FarooqiShahzad Bhatti
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Mar 12, 2019·The British Journal of Dermatology·J E A CommonM A M van Steensel
May 25, 2012·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Nicolas SévèrePierre J Marie
Nov 23, 2012·Médecine sciences : M/S·Nicolas Sévère, Pierre Marie
Dec 10, 2014·Cellular and Molecular Life Sciences : CMLS·Pierre J Marie
Feb 24, 2021·Gene Therapy·Nisreen Mohammed Al-NamnamMohammed Abdullah Alshawsh
Nov 4, 2010·Science Signaling·Hichem Miraoui, Pierre J Marie

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