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Role of hyaluronan in disease

Dr J.R.E. Fraser, Dr T.J. Brown

Hyaluronan is a member of the glycosaminoglycan (GAG) group of polysaccharides which, in varied proportions and combinations with collagens and certain glycoproteins, determine the distinctive structure and function of extracellular matrix in every tissue and organ of all animals. Its primary structure is distinguished from those of its congeners by the absence of sulphate or covalently bound peptide, and by its uniformity in all organisms from bacteria to mammals. Its polymers are by far the largest; its weight-average relative molecular mass ranges between 1 and 10 million in most tissues in contrast with <50,000 in the individual polysaccharide chains of other GAG, which are substituted in peptide cores. Despite this, it is remarkably mobile and freely leaves the tissue matrices through lymphatic channels.

It is most abundant in soft tissues such as skin, and in body fluids such as those of joints and the lining layers of gut, lungs, heart, etc., where the part played by its exceptional viscoelastic properties is most evident. Its functional roles are greatly expanded by specific binding to other matrix components and by a variety of specific cell receptors that influence fundamental behaviour such as motility, mitosis, macromolecular synthesis and other functions. Hyaluronan is especially prominent in sites and phases of cellular proliferation and migration: embryogenesis, regeneration, metamorphosis, tissue repair and some cancers; and in cellular infiltration caused by inflammation. It is involved in some way in virtually every class of disease process; including for example, common skin diseases, arthritis, septicaemia, common immune reactions, liver and lung disease, transplant rejection and cancer. This laboratory is concerned with those aspects of its synthesis, transport and turnover that are most directly involved in these conditions. Current topics of research include the following.

Genetic control of hyaluronan synthesis

This study arose from a unique human condition characterised by accumulation of hyaluronan (hyaluronosis) apparently caused by failure in regulation of its synthesis. We have now identified a similar condition apparently inbred in several animal species. Aims include (a) purification of the active hyaluronan synthase complex from cell membranes to determine primary structure by amino acid sequencing; (b) cloning and sequencing of the hyaluronan synthase gene in this condition and in normal members of the same species.

Cytology and biochemistry of hyaluronan degradation

Hyaluronan turnover is almost entirely effected by receptor-facilitated cellular uptake and catabolism. We have established in vivo all the major biochemical steps of its complete degradation in liver and lymph nodes, the major sites of turnover. We have also identified partial nonenzymatic extracellular degradation in the blood stream. Current studies are being extended to tissues where hyaluronan uptake has been demonstrated but not yet closely examined (kidney and bone marrow); to the kinds of cell most active in hyaluronan uptake and degradation in lymph nodes, spleen, kidney and in the peripheral tissues themselves such as the stroma of the skin.

Medical uses of hyaluronan

  1. Surgical. Hyaluronan enhances wound healing and reduces scarring. In conjunction with the University Dept. of Surgery and St. Vincent's Hospital, we are examining its role in the development of mobile tissue planes in plastic surgery.

  2. Medical. A novel use of hyaluronan is the delivery of appropriate drugs to particular sites; for example, sources of chronic pain, or sites of cancer cell proliferation; in the latter with the object of targeting the drug to upregulated hyaluronan receptors on tumour cells. We are involved in several aspects of this work related to the delivery of hyaluronan at these sites.

Project Areas

  1. Functional and biochemical aspects of hyaluronan with special reference to its role in disease (Dr J.R.E. Fraser and Dr T.J. Brown