Elsevier

Matrix Biology

Volume 35, April 2014, Pages 91-102
Matrix Biology

A decorin-deficient matrix affects skin chondroitin/dermatan sulfate levels and keratinocyte function

https://doi.org/10.1016/j.matbio.2014.01.003Get rights and content
Under a Creative Commons license
open access

Highlights

  • The CS/DS content of Dcn−/− skin is increased but less sulfated compared to wild-type.

  • Dcn−/− CS/DS displayed a reduced Fgf7 and Fgf2 binding capacity.

  • Dcn−/− CS/DS induced keratinocyte proliferation in contrast to wild-type CS/DS.

  • In a co-culture system Dcn−/− CS/DS delayed keratinocyte differentiation.

Abstract

Decorin is a small leucine-rich proteoglycan harboring a single glycosaminoglycan chain, which, in skin, is mainly composed of dermatan sulfate (DS). Mutant mice with targeted disruption of the decorin gene (Dcn−/−) exhibit an abnormal collagen architecture in the dermis and reduced tensile strength, collectively leading to a skin fragility phenotype. Notably, Ehlers–Danlos patients with mutations in enzymes involved in the biosynthesis of DS display a similar phenotype, and recent studies indicate that DS is involved in growth factor binding and signaling. To determine the impact of the loss of DS-decorin in the dermis, we analyzed the glycosaminoglycan content of Dcn−/− and wild-type mouse skin. The total amount of chondroitin/dermatan sulfate (CS/DS) was increased in the Dcn−/− skin, but was overall less sulfated with a significant reduction in bisulfated ΔDiS2,X (X = 4 or 6) disaccharide units, due to the reduced expression of uronyl 2-O sulfotransferase (Ust). With increasing age, sulfation declined; however, Dcn−/− CS/DS was constantly undersulfated vis-à-vis wild-type. Functionally, we found altered fibroblast growth factor (Fgf)-7 and -2 binding due to changes in the micro-heterogeneity of skin Dcn−/− CS/DS. To better delineate the role of decorin, we used a 3D Dcn−/− fibroblast cell culture model. We found that the CS/DS extracts of wild-type and Dcn−/− fibroblasts were similar to the skin sugars, and this correlated with the lack of uronyl 2-O sulfotransferase in the Dcn−/− fibroblasts. Moreover, Ffg7 binding to total CS/DS was attenuated in the Dcn−/− samples. Surprisingly, wild-type CS/DS significantly reduced the binding of Fgf7 to keratinocytes in a concentration dependent manner unlike the Dcn−/− CS/DS that only affected the binding at higher concentrations. Although binding to cell-surfaces was quite similar at higher concentrations, keratinocyte proliferation was differentially affected. Higher concentration of Dcn−/− CS/DS induced proliferation in contrast to wild-type CS/DS. 3D co-cultures of fibroblasts and keratinocytes showed that, unlike Dcn−/− CS/DS, wild-type CS/DS promoted differentiation of keratinocytes. Collectively, our results provide novel mechanistic explanations for the reported defects in wound healing in Dcn−/− mice and possibly Ehlers–Danlos patients. Moreover, the lack of decorin-derived DS and an altered CS/DS composition differentially influence keratinocyte behavior.

Abbreviations

SLRP
small leucine-rich proteoglycan
Dcn−/−
decorin-null mouse
GAG
glycosaminoglycan
DS
dermatan sulfate
CS
chondroitin sulfate
Dcn
mouse decorin gene
Fgf
fibroblast growth factor
ECM
extracellular matrix
EDS
Ehlers–Danlos syndrome
Dse1−/−
dermatan sulfate epimerase 1-null mice

Keywords

Decorin
Dermatan sulfate
SLRP
Extracellular matrix
Fibroblast growth factor

Cited by (0)

This work was financially supported by the German Society for Research (grant DFG SE1431/1-1) to DGS, GRK 1549 International Research Training Group ‘Molecular and Cellular GlycoSciences’ to KN and JR, and NIH grants CA39481 and CA47282 to RVI.

1

These authors contributed equally.