Introduction

Hyaluronan is a non-sulfated glycosaminoglycan (GAG), consisting of repeating units of (b,1-4)-D-glucuronic acid-(b,1-3)-N-acetyl-D-glucosamine. HA occurs normally as a part of the ECM of almost all tissues in a high molecular weight (HMW) polymer (>106 kDa), and the highest concentrations are found in brain, skin and the central nervous system. Originally, it was believed that the physiological function of HA was only structural (1). However, HA is now recognized as a pharmacological signaling molecule. HA functions in a variety of biological processes, including embryonic development (2-4), inflammation, especially with regard to white blood cell function (5-7), angiogenesis (8-11), mammalian fertilization (12,13) and tissue repair/wound healing (1,14-17). HA is also critical for the maintenance of normal tissue elasticity and hydration (5,7) and normal joint function (18). Abnormal expression of HA fragments and/or HA receptors has been shown to play roles in metastasis and survival in several cancer cell types (19-24), tumor vascularization (21,24,25), complications associated with acute lung injury (26-29) and immunological dysfunctions, including asthma and rheumatoid arthritis (5,30-32). At the cellular level HA can induce migration and adhesion (29,33,34), growth and survival (34,35), endocytosis (36,37) and maintenance of endothelial barrier (35).

There is evidence that HA has different functions based on its molecular weight (38,39). In some cases, low molecular weight (LMW) and HMW HA bind the same receptor, but elicit different cellular processes (7,38,39). LMW and HMW HA have also been shown to bind different receptors. HA interacts with a variety of different cell types as well as with many different extracellular molecules collectively known as hyaladherins (40-42). Hyaladherins are involved in cell-cell interactions, cell-matrix interactions, and clearance of HA from blood or tissues. Some of these molecules are found in the ECM and are important in matrix organization. Others are cell surface receptors, including CD44, the receptor for HA-mediated motility (RHAMM), Toll-like receptor 4, layilin, PH-20 protein, LYVE-1, and the HA-associated receptor for endocytosis (HARE) (Table 1).

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