Abstract
Decorin, a small leucine-rich proteoglycan harboring a dermatan sulfate chain at its N-terminus, is involved in regulating matrix organization and cell signaling. Loss of the dermatan sulfate of decorin leads to an Ehlers-Danlos syndrome characterized by delayed wound healing. Decorin-null (Dcn−/−) mice display a phenotype similar to that of EDS patients. The fibrillar collagen phenotype of Dcn−/− mice could be rescued in vitro by decorin but not with decorin lacking the glycosaminoglycan chain. We utilized a 3D cell culture model to investigate the impact of the altered extracellular matrix on Dcn−/− fibroblasts. Using 2D gel electrophoresis followed by mass spectrometry, we identified vimentin as one of the proteins that was differentially upregulated by the presence of decorin. We discovered that a decorin-deficient matrix leads to abnormal nuclear morphology in the Dcn−/− fibroblasts. This phenotype could be rescued by the decorin proteoglycan but less efficiently by the decorin protein core. Decorin treatment led to a significant reduction of the α2β1 integrin at day 6 in Dcn−/− fibroblasts, whereas the protein core had no effect on β1. Interestingly, only the decorin core induced mRNA synthesis, phosphorylation and de novo synthesis of vimentin indicating that the proteoglycan decorin in the extracellular matrix stabilizes the vimentin intermediate filament system. We could support these results in vivo, because the dermis of wild-type mice have more vimentin and less β1 integrin compared to Dcn−/−. Furthermore, the α2β1 null fibroblasts also showed a reduced amount of vimentin compared to wild-type. These data show for the first time that decorin has an impact on the biology of α2β1 integrin and the vimentin intermediate filament system. Moreover, our findings provide a mechanistic explanation for the reported defects in wound healing associated with the Dcn−/− phenotype.
Highlights
Decorin belongs to the small leucine-rich proteoglycans and is covalently linked with a linear glycosaminoglycan (GAG) chain
We discovered that the proteoglycan decorin is required for regulating b1 integrin levels in Dcn2/2 fibroblast in order to stabilize the vimentin intermediate filaments (IF) system
To investigate the effects of decorin and dermatan sulfate on cell function, we used an in-vivo-like cell culture system consisting of Dcn2/2 dermal fibroblasts synthesising their own collagen-rich matrix and supplemented with decorin or decorin protein core
Summary
Decorin belongs to the small leucine-rich proteoglycans and is covalently linked with a linear glycosaminoglycan (GAG) chain. Depending on the tissue the GAG chain is either chondroitin or dermatan sulfate (CS/DS). The stereochemistry of the glycosidic linkage in CS is (bD-GlcA1’.39 bD-GalNAc1’-.49-). In DS the D-GlcA is epimerized to Liduronic acid (L-IdoA) with a glycosidic stereochemistry (aLIdoA1’-.39 bD-GalNAc1’-.49-). The function of decorin is diverse and ranges from modulating collagen fibrillogenesis [1,2] and matrix organization [3] to cell adhesion and migration [4]. Decorin is able to decrease the amount of miR-21 and IL-10 and to stimulate the production of the proinflammatory tumor suppressor PDCD4 [13]. Decorin can modulate transforming growth factor-b bioavailability [14]
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