Fraser JRE, Laurent TC, Laurent UBG (Monash University, Clayton, Victoria, Australia; and University of Uppsala, Uppsala, Sweden). Hyaluronan: its nature, distribution, functions and turnover (Minisymposium: Hyaluronan). J Intern Med 1997; 242: 27–33. Hyaluronan is a polysaccharide found in all tissues and body fluids of vertebrates as well as in some bacteria. It is a linear polymer of exceptional molecular weight, especially abundant in loose connective tissue. Hyaluronan is synthesized in the cellular plasma membrane. It exists as a pool associated with the cell surface, another bound to other matrix components, and a largely mobile pool. A number of proteins, the hyaladherins, specifically recognize the hyaluronan structure. Interactions of this kind bind hyaluronan with proteoglycans to stabilize the structure of the matrix, and with cell surfaces to modify cell behaviour. Because of the striking physicochemical properties of hyaluronan solutions, various physiological functions have been assigned to it, including lubrication, water homeostasis, filtering effects and regulation of plasma protein distribution. In animals and man, the half‐life of hyaluronan in tissues ranges from less than 1 to several days. It is catabolized by receptor‐mediated endocytosis and lysosomal degradation either locally or after transport by lymph to lymph nodes which degrade much of it. The remainder enters the general circulation and is removed from blood, with a half‐life of 2–5 min, mainly by the endothelial cells of the liver sinuoids.

Hyaluronan is a major component of synovial tissue and fluid as well as other soft connective tissues. It is a high-Mr polysaccharide which forms entangled networks already at dilute concentrations (< 1 mg/mL) and endows its solutions with unique rheological properties. Physiological functions of hyaluronan (lubrication, water homeostasis, macromolecular filtering, exclusion, etc.) have been ascribed to the properties of these networks. Recently a number of specific interactions between hyaluronan and a group of proteins named hyaladherins have also pointed towards a role of hyaluronan in recognition and the regulation of cellular activities. Many more or less well documented hypotheses have been proposed for the function of hyaluronan in joints, for example, that it should lubricate, protect cartilage surfaces, scavenge free radicals and debris, keep the joint cavities open, form flow barriers in the synovium and prevent capillary growth.

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Hyaluronan is a connective tissue polysaccharide which has also been found in blood serum in concentrations < 100 micrograms/L (average 30-40 micrograms/L in middle-aged persons). The serum level is regulated by the influx of the polysaccharide from the tissues via lymph and its receptor-mediated clearance by liver endothelial cells. Markedly high serum levels are noted in certain liver diseases, especially in patients with cirrhosis, when the clearance is impaired. In these cases serum hyaluronan can be used to follow the development of the disease. Serum hyaluronan is also a sensitive marker for impending rejection of liver transplants. Patients with rheumatoid arthritis constitute another major group with increased serum hyaluronan, but in this case the level varies markedly during the day corresponding to physical activity. There are good indications that in these subjects the excess hyaluronan comes from the joints. Under stringent sampling conditions of serum it should be possible to extract interesting information on the inflammatory joint process. Increased hyaluronan levels are also seen in other inflammatory diseases and it is of special interest that high hyaluronan levels in patients with septic conditions is a sign of poor prognosis. Certain tumours, notably Wilms' tumour and mesothelioma, produce factors which activate synthesis of hyaluronan and increase its serum level. Rare hereditary diseases with disturbances of hyaluronan metabolism and elevated blood levels have also been discovered, e.g. Werner's syndrome and cutaneous hyaluronanosis. Information accumulated during the last decade regarding the metabolism of hyaluronan has made this polysaccharide an interesting clinical marker for a number of pathological conditions.

A radioassay for sodium hyaluronate using high-affinity binding protein from bovine cartilage has been modified for serum analysis. The accuracy of the method was checked by isotope dilution experiments and by recovery studies with exogenous hyaluronate. The between-assay standard deviation in the determination is 15-20%. The concentration of sodium hyaluronate in healthy adults (blood donors) is in the range of 10 to 100 micrograms/l with a mean value in the order of 30 to 40 micrograms/l. This is a lower concentration than previously reported. The same level was found in young people. Higher hyaluronate concentrations were noted in persons above 50 years of age. Analysis of plasma showed a slightly higher average hyaluronate level (5%) than in serum from the same persons. There were no notable sex differences. Analysis of serum and plasma from adult animals (rat, rabbit, dog, pig, goat, sheep, cow and horse) gave hyaluronate concentrations of the same order or higher than in human serum.