Biodiversity of CS–proteoglycan sulphation motifs: chemical messenger recognition modules with roles in information transfer, control of cellular behaviour and tissue morphogenesis

Abstract

Chondroitin sulphate (CS) glycosaminoglycan chains on cell and extracellular matrix proteoglycans (PGs) can no longer be regarded as merely hydrodynamic space fillers. Overwhelming evidence over recent years indicates that sulphation motif sequences within the CS chain structure are a source of significant biological information to cells and their surrounding environment. CS sulphation motifs have been shown to interact with a wide variety of bioactive molecules, e.g. cytokines, growth factors, chemokines, morphogenetic proteins, enzymes and enzyme inhibitors, as well as structural components within the extracellular milieu. They are therefore capable of modulating a panoply of signalling pathways, thus controlling diverse cellular behaviours including proliferation, differentiation, migration and matrix synthesis. Consequently, through these motifs, CS PGs play significant roles in the maintenance of tissue homeostasis, morphogenesis, development, growth and disease. Here, we review (i) the biodiversity of CS PGs and their sulphation motif sequences and (ii) the current understanding of the signalling roles they play in regulating cellular behaviour during tissue development, growth, disease and repair.

Glycosaminoglycan and Proteoglycan Biotherapeutics in Articular Cartilage Protection and Repair Strategies: Novel Approaches to Visco‐supplementation in Orthobiologics

“…[13,15,36,69] As already noted, aggrecan is the major cartilage PG responsible for the imbibition of water into cartilage which is the basis of cartilages ability to act as a weight bearing tissue (Figure 3), perlecan is also a prominent pericellular PG ( Figure 4). These have been recently reviewed.…”

“…[36] GAG evolution over 500 million years of vertebrate and invertebrate evolution [37] has selected for GAGs equipped with molecular recognition and information transfer properties. [13,14,[39][40][41][42][43][44] [38][39][40] Thus GAGs and PGs evolved which have regulatory properties over downstream cell-signaling pathways and gene expression networks essential for physiological life processes.…”

“…[51,52] Nano-scale biomatrices have been developed for studies of such glycocalyx interactions [51] and GAG microarrays have aided in the elucidation of GAG sulphation patterns required to drive such processes. [13,28,39,41,43,55] [5,18,30,54] GAG side chains in PGs are variably sulfated and have interactive properties with growth factors, chemokines, cytokines, morphogenetic proteins, and structural matrix components, which aid in the stabilization and development of tissues.…”

“…Lumican, fibromodulin, and keratocan have 3-4 N-linked KS chains located within their LRR regions. [13] Copyright 2018, Portland Press. The SLRPs regulate tissue organization, cellular proliferation, adhesion, and responses to growth factors and cytokines [77] in inflammation, [16] cell growth, tissue morphogenesis, and innate immunity.…”

“…[13,39,48,122,123] HA has important progenitor cell regulatory properties operative in embryonic and fetal development and is a common component of stem cell niches. The CS sulphation motifs have information and cell regulatory properties similar to other GAGs.…”