Aggrecan, the Primary Weight-Bearing Cartilage Proteoglycan, Has Context-Dependent, Cell-Directive Properties in Embryonic Development and Neurogenesis: Aggrecan Glycan Side Chain Modifications Convey Interactive Biodiversity

Anthony J Hayes,James Melrose

doi:10.3390/biom10091244

Abstract

This review examines aggrecan’s roles in developmental embryonic tissues, in tissues undergoing morphogenetic transition and in mature weight-bearing tissues. Aggrecan is a remarkably versatile and capable proteoglycan (PG) with diverse tissue context-dependent functional attributes beyond its established role as a weight-bearing PG. The aggrecan core protein provides a template which can be variably decorated with a number of glycosaminoglycan (GAG) side chains including keratan sulphate (KS), human natural killer trisaccharide (HNK-1) and chondroitin sulphate (CS). These convey unique tissue-specific functional properties in water imbibition, space-filling, matrix stabilisation or embryonic cellular regulation. Aggrecan also interacts with morphogens and growth factors directing tissue morphogenesis, remodelling and metaplasia. HNK-1 aggrecan glycoforms direct neural crest cell migration in embryonic development and is neuroprotective in perineuronal nets in the brain. The ability of the aggrecan core protein to assemble CS and KS chains at high density equips cartilage aggrecan with its well-known water-imbibing and weight-bearing properties. The importance of specific arrangements of GAG chains on aggrecan in all its forms is also a primary morphogenetic functional determinant providing aggrecan with unique tissue context dependent regulatory properties. The versatility displayed by aggrecan in biodiverse contexts is a function of its GAG side chains.

Highlights

A vast amount has been written over the last five decades on aggrecan’s structure (Figure 1) and function in weight-bearing connective tissues such as hyaline cartilage and intervertebral disc (IVD) in health and disease [1,2,3,4,5,6,7,8]
This review shows that aggrecan is an important functional component of articular cartilage and is depleted in OA cartilage
The variable functional attributes of aggrecan in particular tissue contexts is due to the diverse structure of its attached glycan side chains, allowing it to act as a space-filling molecule with an ability to entrap water in weight-bearing tissues such as articular cartilage and IVD and as an interactive molecule with morphogens, growth factors and cells in growth plate cartilage and embryonic tissues

Summary

Introduction

A vast amount has been written over the last five decades on aggrecan’s structure (Figure 1) and function in weight-bearing connective tissues such as hyaline cartilage and intervertebral disc (IVD) in health and disease [1,2,3,4,5,6,7,8]. This review aims to rectify this deficiency but cannot be meaningfully undertaken without first covering aggrecan’s functional attributes in weight-bearing tissues that contribute to matrix stabilisation. This diversity in aggrecan’s functional properties is due to modifications in its glycosaminoglycan (GAG) side chains which equip it with unique ligand interactivity in specific developmental contexts. 7-D-4 reactivity are susceptible to chondroitinase ABC digestion; in graded partial digestions, the 6-C-3 and 4-C-3 reactivity can be selectively removed leaving the 7-D-4 reactive region intact This is susceptible to chondroitinase ABC, and exhaustive digestion conditions eventually lead to generation of the unsaturated 3-B-3(+) and 2-B-6(+) stub epitopes attached to the linkage region, as shown in this diagram. In (f), the structures shown hypothetical many features such as the sulphation positions on GAGs are variable; the depictions shown are generalisations based on literature data

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Results

Conclusion