Abstract
Dermal fibroblasts derived from types I and IV Ehlers-Danlos syndrome (EDS) patients, carrying mutations in COL5A1 and COL3A1 genes, respectively, synthesize aberrant types V and III collagen (COLL) and show defective organization of these proteins into the extracellular matrix (ECM) and high reduction of their functional receptor, the alpha(2)beta(1) integrin, compared with control fibroblasts. EDS cells also show reduced levels of fibronectin (FN) in the culture medium and lack an FN fibrillar network. Finally, EDS cells prevalently organize alpha(v)beta(3) integrin instead of alpha(5)beta(1) integrin. The alpha(v)beta(3) integrin, distributed on the whole EDS cell surface, shows FN binding and assembly properties when the cells are treated with purified FN. Treatment of EDS cells with purified COLLV or COLLIII, but not with FN, restores the control phenotype (COLL(+), FN(+), alpha(v)beta(3)(-), alpha(5)beta(1)(+), alpha(2)beta(1)(+)). Function-blocking antibodies to COLLV, COLLIII, or alpha(2)beta(1) integrin induce in control fibroblasts an EDS-like phenotype (COLL(-), FN(-), alpha(v)beta(3)(+), alpha(5)beta(1)(-), alpha(2)beta(1)(-)). These results show that in human fibroblasts alpha(2)beta(1) integrin organization and function are controlled by its ligand, and that the alpha(2)beta(1)-COLL interaction, in turn, regulates FN integrin receptor recruitment: high alpha(2)beta(1) integrin levels induce alpha(5)beta(1) integrin organization, while low alpha(2)beta(1) integrin levels lead to alpha(v)beta(3) integrin organization.
Highlights
Dermal fibroblasts derived from types I and IV EhlersDanlos syndrome (EDS) patients, carrying mutations in COL5A1 and COL3A1 genes, respectively, synthesize aberrant types V and III collagen (COLL) and show defective organization of these proteins into the extracellular matrix (ECM) and high reduction of their functional receptor, the ␣21 integrin, compared with control fibroblasts
Mutations in COL5A1 and COL3A1 Genes Affect the Organization of COLLs into the ECM and Clustering of ␣21 Integrin Receptor in Cultured Fibroblasts—We analyzed the assembly of COLLV and COLLIII in the ECM in EDSI and EDSIV fibroblasts, which carry mutations in COL5A1 and COL3A1, respectively, as compared with control fibroblasts
In this work we studied the effect of mutations in COL5A1 and COL3A1 genes, leading in vivo to classical (EDSI) and vascular (EDSIV) EDS, on cultured skin fibroblast phenotypes
Summary
Dermal fibroblasts derived from types I and IV EhlersDanlos syndrome (EDS) patients, carrying mutations in COL5A1 and COL3A1 genes, respectively, synthesize aberrant types V and III collagen (COLL) and show defective organization of these proteins into the extracellular matrix (ECM) and high reduction of their functional receptor, the ␣21 integrin, compared with control fibroblasts. Mutations in COL5A1 and COL3A1 Genes Affect the Organization of COLLs into the ECM and Clustering of ␣21 Integrin Receptor in Cultured Fibroblasts—We analyzed the assembly of COLLV and COLLIII in the ECM in EDSI and EDSIV fibroblasts, which carry mutations in COL5A1 and COL3A1, respectively, as compared with control fibroblasts.
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