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Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
FGF2 effects in periosteal fibroblasts bearing the FGFR2 receptor Pro253 Arg mutation
Cinzia Lilli1, Catia Bellucci, Tiziano Baroni
1Department of Exp. Med. and Bioch. Sciences, University of Perugia, via del Giochetto, 06100 Perugia, Italy.
Aim:
A growing number of mutations mapped in the receptor gene for fibroblast growth factor have been implicated in several cranial development disorders including the Apert and Crouzon syndromes. The present paper investigated cellular mechanisms underlying Apert phenotype, by analyzing the effects of FGF2 in primary cultures of Apert periosteal fibroblasts carrying the FGFR2 Pro253Arg mutation.
Results:
FGF2 administration significantly decreased extracellular matrix production in mutant cells by stimulating degradative enzymatic activities. Gene expression analysis revealed that decorin and biglycan, two proteoglycans involved in collagen fibrillogenesis, were more expressed in mutant cells and down-regulated by FGF2. FGF2 receptor binding showed little differences in high affinity receptor counts between mutant and wild-type cells, while we showed for the first time that low affinity receptors are significantly fewer in mutant cells. Differences were found in Crouzon syndrome, where both high and low affinity receptor counts were up-regulated.
Conclusions:
The different mutation and low affinity receptor regulation in mutant receptors support the hypothesis that the impact on the activity of the ligand-receptor complex could allow distinct modes of FGF2 activation in Apert and Crouzon syndromes, which interfere with the FGFR2 signalling cascade.
Insights
Fibroblast growth factor 2 (FGF2) impacts extracellular matrix production in Apert syndrome fibroblasts by altering low-affinity receptor levels. This suggests distinct FGF2 signaling in Apert and Crouzon syndromes.
Area of Science:
- Cell Biology
- Genetics
- Developmental Biology
Background:
- Mutations in fibroblast growth factor receptor 2 (FGFR2) are linked to cranial development disorders like Apert and Crouzon syndromes.
- Understanding the cellular mechanisms of these syndromes is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the cellular mechanisms underlying the Apert phenotype.
- To analyze the effects of FGF2 on primary cultures of Apert periosteal fibroblasts with the FGFR2 Pro253Arg mutation.
Main Methods:
- Primary cell culture of Apert periosteal fibroblasts.
- Administration of FGF2 and analysis of extracellular matrix production.
- Gene expression analysis of decorin and biglycan.
- FGF2 receptor binding assays to quantify high and low affinity receptors.
Main Results:
- FGF2 decreased extracellular matrix production in mutant cells by stimulating degradative enzymes.
- Decorin and biglycan were upregulated in mutant cells and downregulated by FGF2.
- Low-affinity FGF2 receptors were significantly fewer in Apert mutant cells compared to wild-type.
- Crouzon syndrome cells showed upregulated high and low affinity FGF2 receptors.
Conclusions:
- Differential regulation of low-affinity receptors in Apert syndrome fibroblasts suggests a distinct FGF2 activation mechanism.
- These findings support the hypothesis that altered FGF2 ligand-receptor complex activity interferes with FGFR2 signaling in Apert and Crouzon syndromes.
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