Proteoglycans as organizers of the intercellular matrix.

Introduction The evolution of multicellular organisms made necessary the development of an extracellular matrix to protect cells and to bind them together in a spatial arrangement required for specialized anatomical and physiological functions. Thus the extent of the matrix and how it is organized in different parts of the body depend on the specialized functions of cells. The matrix in its turn influences the sorting and organization of cells during embryonic development of animals (see Hay, 198 1). Collagen is the principal structural protein of animals, a primitive form of which was evolved by Porifera (Mathews, 1967; Adams, 1978). It has proved so suitable that it is highly conserved and remains the prime structural protein of higher animals, providing the fibrous framework for the body. The extracellular matrix also contains polyanionic macromolecules which fill the interfibrillar space and complement the role of collagen by retaining water in the tissue and controlling its flow (see below). In Nature, polyanions predominate in the pericellular environment, and it has been suggested (Scott, 1975, 1979) that this predominance arose because the Donnan effects of polyanions would exclude from their domains the extremely reactive hydrated electrons produced by ionizing radiations on water. Pericellular polyanions would thus have protected primitive organisms from damage by hydrated electrons and their reactive products generated by the intense radiation that reached the biosphere when there was a thinner protective ozone layer because there was less oxygen in the atmosphere. The acidic polysaccharides of the extracellular matrix of vertebrates are much less diverse than those of invertebrates (Mathews, 1967). In mammals there are a limited number, based on differences in repeating disaccharide units of which they are composed. They are collectively known as glycosaminoglycans and are long unbranched chains with many carboxy and/or sulphate groups made up of disaccharide units of hexosamine and uronic acid or hexosamine and galactose (for reviews, see Muir & Hardingham, 1975: Hardingham, 198 1). However, with the probable exception of hyaluronic acid, all glycosaminoglycans are attached at the reducing end to specific proteins to form large macromolecules known as proteoglycans, a term introduced in 1967 (see Balazs & Gibbs, 1970). Several glycosaminoglycan chains are attached laterally to the protein, from which they extend outwards like a bottle brush owing to electrostatic repulsion of their negatively charged groups. The physical properties of different tissues of the body depend mainly on differences in the proportion of collagen to proteoglycan. which varies widely, and also on the type of proteoglycan and collagen and how these are organized in the matrix. The specific anatomical distribution of different proteoglycans and collagen implies that they have different functions, although these are not yet known precisely. The organizing functions of proteoglycans can be roughly separated into space-filling functions and specific interactions; however, much more is known about the former than the latter. The space-filling role of proteoglycans is very important in cartilage. where the concentration of proteoglycans is higher than in any other tissue. Most progress has therefore been made in elucidating structure and function of proteoglycans of cartilage, which have particular features necessary for this space-filling role, which will be discussed in detail below.