HYALURONIC ACID, RECEPTOR CD44, AND THEIR ROLE IN DIABETES COMPLICATIONS
N. Yu. Yevdokimova
Hyaluronic acid (HA) is a straight chain glycosaminoglycan polymer composed of repeating units of the disaccharide [-D-glucuronic acid-?1,3-N-acetyl-D-glucosamine-?1,4-]n, and is found in vertebrates and certain microorganisms. The molecular weight of HA chains is usually equal to ~1–10 and MDa, n > 103-4, although it can exists as oligosaccharides under some physiological and pathological conditions. HA resides on the cell surface or in the extracellular space, but it also occurred inside the mammalian cells. HA is synthesized in mammals by three enzymes with polymers of varying chain length. The biological functions of HA include the maintenance of elastoviscosity of liquid connective tissues, control of tissue hydration, supramolecular assembly of proteoglycans in the extracellular matrix and besides numerous receptor-mediated functions in cell attachment, mitosis, migration, tumor development, wound healing and inflammation. The extensive repertoire of biological functions of HA corresponds to the existence of a large repertoire of HA-binding proteins (hyaladherins). Many hyaladherins contain a common structural domain, termed a Link module, which is involved in ligand binding. The most important member of the Link module superfamily is the main HA receptor, CD44. CD44 has diverse functions including not only the organization and metabolism of extracellular matrix, but also engage the cytoskeleton and co-ordinate signaling events to enable the cell responce to changes in the environment. HA has an extraordinary high rate of turnover, and at the cellular level it is considered to be degraded progressively by a series of enzymatic reactions that generate polymers of decreasing sizes. HA biological effects are known to be determined by the polymer size and depend on the cell type. For example, the native high molecular weight HA is anti-angiogenic, while its degradation products (6–20 saccharides) stimulate endothelial cell proliferation, migration and differentiation. In contrast, these fragments inhibit the proliferation of vascular smooth muscle cells, whereas high molecular weight HA promotes cell growth and migration. The dysregulation of HA metabolism is a typical feature of diabetes complications, and increased glucose level is considered to be the main cause of this phenomenon. The HA depolymerization due to the effect of free radicals and advanced glycation end products leads to the vitreous body liquefaction, and may be the reason of the proliferative retinopathy in diabetes. The enrichment of extracellular matrix with high molecular weight HA under the action of high glucose level was demonstrated for vascular smooth muscle cells, skin fibroblasts, endothelial and mesangial cells. This effect is considered to accelerate the development of atherosclerosis stimulating the proliferation of vascular smooth muscle cells, and to promote the transformation of acute wounds into chronic ulcers deepening the pathological state of dermal fibroblasts in diabetes. And, on the contrary, the accumulation of high molecular weight HA on the surface of endothelial cells may have positive value for the glycocalyx integrity. Since high molecular weight HA is known to possess the anti-inflammatory and anti-fibrotic effect, the enrichment of mesangial matrix with it may represent an endogenous mechanism to limit renal injury in diabetes. Thus, the investigation of HA metabolism in diabetes mellitus emphasizes the dependence of HA biological effects on cell type and demonstrates the importance of this molecule for tissue homeostasis.
Key words: hyaluronic acid, CD44, extracellular matrix, vascular smooth muscle cells, dermal fibroblasts, endothelial cells, mesangial cells, diabetes mellitus.
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