Hyaluronan (also called hyaluronic acid or hyaluronate) is a glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is one of the chief components of the extracellular matrix, contributes significantly to cell proliferation and migration, and may also be involved in the progression of some malignant tumors.

Functions

Until the late 1970s, hyaluronan was described as a "goo" molecule, a ubiquitous carbohydrate polymer that comprised the extracellular matrix. For example, hyaluronan is a major component of the extracellular matrix that constitutes synovial fluid. Along with lubricin , it is one of the fluid's main lubricating components. It helps protect joints by increasing the viscosity of the fluid and by making the cartilage between bones more elastic.

While it is found in large numbers in extracellular matrices, hyaluronan also contributes to tissue hydrodynamics, movement and proliferation of cells, and participates in a number of cell surface receptor interactions, notably those including its primary receptor in vivo, CD44 .

Hyaluronan's contribution to tumor growth may be due to its interaction with CD44. CD44, the chief in vivo hyaluronan receptor, participates in cell adhesion interactions required by tumor cells. Some of the enzymes that break down hyaluronan are known tumor suppressants; paradoxically, the gene for hyaluronidase-2 is an oncogene and promotes tumor growth.

Structure

The chemical structure of hyaluronan was determined in the 1950s in the laboratory of Karl Meyer . Hyaluronan is a polymer of disaccharides themselves composed of D-glucuronic acid and D-N-acetylglucosamine, linked together via alternating beta-1,4 and beta-1,3 glycosidic bonds. Polymers of hyaluronan can range in size from 10² to 10⁴ kDa in vivo.

Hyaluronan is energetically stable in part because of the stereochemistry of its component disaccharides. Bulky groups on each sugar molecule are in sterically favored positions while the smaller hydrogens assume the less favorable axial positions.

Synthesis

Hyaluronan is synthesized by a class of integral membrane proteins called hyaluronan synthases , of which vertebrates have three types: HAS1, HAS2, and HAS3. These enzymes lengthen hyaluronan by repeatedly adding glucuronic acid and N-acetylglucosamine to the nascent polysaccharide.

Degradation

Hyaluronan is degraded by a family of enzymes called hyaluronidases. In humans, there are at least seven types of hyaluronidase-like enzymes, several of which are tumor suppressors.

Medical applications

Since 1987, sodium hyaluronate has been used to treat mild to moderate osteoarthritis in several contries, most notably Japan and Italy. Its exact mechanism of action is not yet known; recent evidence suggests that it blocks prostaglandin E2 production, thereby reducing inflammation and consequent pain.

In some cancers, hyaluronan levels correlate well with malignancy and poor prognosis. Hyaluronan is thus often used as a tumor marker for prostate and breast cancer. It may also be used to monitor the progression of the disease.

Hyaluronan may also be used postoperatively to induce tissue healing, notably after cataract surgery. Current models of wound healing propose that larger polymers of hyaluronic acid appear in the early stages of healing to physically make room for white blood cells, which mediate the immune response.

Hyaluronan is also now a common skin care ingredient.

Etymology

Chosen by Meyer in 1934, the name hyaluronic acid comes from hyaloid (meaning "vitreous") and uronic acid . The term hyaluronate refers to the conjugate base of hyaluronic acid. Because the molecule typically exists in vivo in its polyanionic form, it is most commonly referred to as hyaluronan.

References

• Auvinen P, Tammi R, Parkkinen J, Tammi M, Agren U, Johansson R, Hirvikoski P, Eskelinen M, Kosma VM. "Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival." Am J Pathol. 2000 Feb;156(2):529-36. PMID 10666382
• Toole BP. "Hyaluronan in morphogenesis." J Intern Med. 1997 Jul;242(1):35-40. PMID 9260564
• Medical applications of hyaluronan, from the Glycoforum

External links

• The Glycoforum