Abstract

The extracellular matrix (ECM) is a complex mixture composed of fibrillar collagens as well as additional protein and carbohydrate components. Proteoglycans (PGs) contribute to the heterogeneity of the ECM and play an important role in its structure and function. While the small leucine rich proteoglycans (SLRPs), including decorin and lumican, have been studied extensively as mediators of collagen fibrillogenesis and organization, the function of large matrix PGs in collagen matrices is less well known. In this study, we showed that different matrix PGs have distinct roles in regulating collagen behaviors. We found that versican, a large chondroitin sulfate PG, promotes collagen fibrillogenesis in a turbidity assay and upregulates cell-mediated collagen compaction and reorganization, whereas aggrecan, a structurally-similar large PG, has different and often opposing effects on collagen. Compared to versican, decorin and lumican also have distinct functions in regulating collagen behaviors. The different ways in which matrix PGs interact with collagen have important implications for understanding the role of the ECM in diseases such as fibrosis and cancer, and suggest that matrix PGs are potential therapeutic targets.

Highlights

  • The extracellular matrix (ECM) is a complex mixture composed of fibrillar collagens as well as additional protein and carbohydrate components

  • Matrix proteoglycans have different effects on collagen fibrillogenesis in vitro. Proteoglycans and their GAG side chains have been well studied as collagen ­regulators[26] through the use of in vitro spectrophotometric assays whereby the turbidity of a collagen solution is measured as gelation p­ roceeds[27], generating a sigmoidal curve with a lag phase followed by a growth phase and after complete gelation, a plateau

  • small leucine rich proteoglycans (SLRPs), which belong to the group of matrix PGs, have opposing effects on collagen behaviors when compared to versican

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Summary

Introduction

The extracellular matrix (ECM) is a complex mixture composed of fibrillar collagens as well as additional protein and carbohydrate components. The structure and organization of these networks can be regulated by cell-generated f­orces[2] and by interactions with other ECM components including proteoglycans (PGs) and glycosaminoglycans (GAGs)[3,4]. PGs are highly negatively charged (especially the large PGs with multiple GAG side chains) and, in part through their interactions with collagen and water, contribute to tissue mechanics by swelling and stiffening tissues, which enables them to resist compression and to retain ­water[5] They are important regulators of ECM related diseases including inflammation, fibrosis and c­ ancer[6,7]. We report that different matrix PGs (even within a particular family) have distinct roles in the regulation of collagen behavior, suggesting that the relative expression of individual matrix PGs may be an important regulator of tissue function and cell behavior in disease

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