Type III and V collagens modulate the expression and assembly of EDA(+) fibronectin in the extracellular matrix of defective Ehlers-Danlos syndrome fibroblasts.

Alternative splicing of EDA fibronectin (FN) region is a cell type- and development-regulated mechanism controlled by pathological processes, growth factors and extracellular matrix (ECM). Classic and vascular Ehlers-Danlos syndrome (cEDS and vEDS) are connective tissue disorders caused by COL5A1/COL5A2 and COL3A1 gene mutations, leading to an in vivo abnormal collagen fibrillogenesis and to an in vitro defective organisation in the ECM of type V (COLLV) and type III collagen (COLLIII). These defects induce the FN-ECM disarray and the decrease of COLLs and FN receptors, the α2β1 and α5β1 integrins. Purified COLLV and COLLIII restore the COLL-FN-ECMs in both EDS cell strains.,Real-time PCR, immunofluorescence microscopy, and Western blotting were used to investigate the effects of COLLs on FN1 gene expression, EDA region alternative splicing, EDA(+)-FN-ECM assembly, α5β1 integrin and EDA(+)-FN-specific α9 integrin subunit organisation, α5β1 integrin and FAK co-regulation in EDS fibroblasts.,COLLV-treated cEDS and COLLIII-treated vEDS fibroblasts up-regulate the FN1 gene expression, modulate the EDA(+) mRNA maturation and increase the EDA(+)-FN levels, thus restoring a control-like FN-ECM, which elicits the EDA(+)-FN-specific α9β1 integrin organisation, recruits the α5β1 integrin and switches on the FAK binding and phosphorylation.,COLLs regulate the EDA(+)-FN-ECM organisation at transcriptional and post-transcriptional level and activate the α5β1-FAK complexes. COLLs also recruit the α9β1 integrin involved in the assembly of the EDA(+)-FN-ECM in EDS cells.,The knowledge of the COLLs-ECM role in FN isotype expression and in EDA(+)-FN-ECM-mediated signal transduction adds insights in the ECM remodelling mechanisms in EDS cells.