Linked Life Data

20124286

Source:http://linkedlifedata.com/resource/pubmed/id/20124286

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2010-4-8
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1460-2083
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
19
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1678-89
pubmed:meshHeading
pubmed-meshheading:20124286-Acrocephalosyndactylia, pubmed-meshheading:20124286-Blotting, Western, pubmed-meshheading:20124286-DNA Mutational Analysis, pubmed-meshheading:20124286-DNA Primers, pubmed-meshheading:20124286-Fetus, pubmed-meshheading:20124286-Gene Expression Profiling, pubmed-meshheading:20124286-Humans, pubmed-meshheading:20124286-Immunohistochemistry, pubmed-meshheading:20124286-Immunoprecipitation, pubmed-meshheading:20124286-Microarray Analysis, pubmed-meshheading:20124286-Mutation, pubmed-meshheading:20124286-Osteoblasts, pubmed-meshheading:20124286-Receptor, Epidermal Growth Factor, pubmed-meshheading:20124286-Receptor, Fibroblast Growth Factor, Type 2, pubmed-meshheading:20124286-Receptor, Platelet-Derived Growth Factor alpha, pubmed-meshheading:20124286-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:20124286-Signal Transduction, pubmed-meshheading:20124286-Up-Regulation
pubmed:year
2010
pubmed:articleTitle
Increased EFG- and PDGFalpha-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis.
pubmed:affiliation
Laboratory of Osteoblast Biology and Pathology, Inserm U606, Paris, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't