Biology of hyaluronan: Insights from genetic disorders of hyaluronan metabolism

Abstract

Hyaluronan is a rapidly turned over component of the vertebrate extracellular matrix. Its levels are determined, in part, by the hyaluronan synthases, HAS1, HAS2, and HAS3, and three hyaluronidases, HYAL1, HYAL2 and HYAL3. Hyaluronan binding proteins also regulate hyaluronan levels although their involvement is less well understood. To date, two genetic disorders of hyaluronan metabolism have been reported in humans: HYAL1 deficiency (Mucopolysaccharidosis IX) in four individuals with joint pathology as the predominant phenotypic finding and HAS2 deficiency in a single person having cardiac pathology. However, inherited disorders and induced mutations affecting hyaluronan metabolism have been characterized in other species. Overproduction of hyaluronan by HAS2 results in skin folding and thickening in shar-pei dogs and the naked mole rat, whereas a complete deficiency of HAS2 causes embryonic lethality in mice due to cardiac defects. Deficiencies of murine HAS1 and HAS3 result in a predisposition to seizures. Like humans, mice with HYAL1 deficiency exhibit joint pathology. Mice lacking HYAL2 have variably penetrant developmental defects, including skeletal and cardiac anomalies. Thus, based on mutant animal models, a partial deficiency of HAS2 or HYAL2 might be compatible with survival in humans, while complete deficiencies of HAS1, HAS3, and HYAL3 may yet be recognized.

Keywords: Hyaluronan; Hyaluronan synthase 2; Hyaluronidase; Hyaluronidase 1; Hyaluronidase 2; Mucopolysaccharidosis.

Figure 1

Hyaluronan synthesis. Uridine diphosphate (UDP)-linked sugar substrates, glucuronic acid (GlcA) and N-acetylglucosamine (GlcNAc), are sequentially added to the reducing end of the growing HA chain at the cytoplasmic aspect of the cell membrane through the action of hyaluronan synthase (HAS). The resulting sugar polymer is extruded into the extracellular matrix surrounding the cell.

Figure 2

Hyaluronidase function. Mammalian hyaluronidases are endoglycosidases that hydrolyze the β1→4 linkage between the GlcNAc and GlcA disaccharide units that make up HA. This results in non-reducing and reducing termini; the non-reducing sugar becomes a substrate for the exoglycosidase β-glucuronidase.

Figure 3

Proposed model for hyaluronan breakdown. Hyaluronan (HA) bound by a cell- or matrix-associated receptor such as CD44, HARE, or LYVE-1 is proposed to be hydrolyzed to intermediate-sized fragments by the GPI-linked HYAL2. The resulting fragments are then internalized by receptor-mediated endocytosis and transported to lysosomes. Once inside the lysosome, further degradation takes place through the action of the acid-active HYAL1. HYAL1 cleaves the intermediate-sized HA fragments to smaller fragments such that they become substrates for the sequential action of the exoglycosidases, β-glucuronidase (Gluc) and β-N-acetylhexosaminidase (Hex) which hydrolyze terminal GlcA and GlcNAc, respectively. The role of HYAL3 is unclear although its overexpression increases HYAL1 activity in cell culture based studies.