Hyaluronan

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. Upregulation of CD44 itself is widely accepted as a marker of cell activation in lymphocytes.

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. Its structure has been determined by both NMR and x-ray crystallography.

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. The degradation products of hyaluronan, the oligosaccharides and very low molecular weight hyaluronan, exhibit pro-angiogenic properties.

Medical applications

Hyaluronan is naturally found in many tissues of the body such as skin, cartilage, and the vitreous humor. It is therefore well suited to biomedical applications targeting these tissues. The first hyaluronan biomedical product, Healon, was developed in the 1970s and 1980s and is approved for use in ophthalmic surgery (i.e. corneal transplantation, cataract surgery, glaucoma surgery and retinal attachment surgery)Other biomedical companies also produce brands of hyaluronan for ophthalmic surgery ^*. Hyaluronan is also used to treat osteoarthritis of the knee ^*^*^*. Such treatments are administered as a course of injections into the knee joint and are believed to supplement the viscosity of the joint fluid thereby lubricating the joint, cushioning the joint and producing an analgesic effect. It has also been suggested that hyaluronan has positive biochemical effects on cartilage cells. However, some placebo controlled studies have cast doubt on the efficacy of hyaluronan injections and hyaluronan is recommended primarily as a last alternative to surgery.

Due to its high biocompatibility and its common presence in the extracellular matrix of tissues, hyaluronan is gaining popularity as a biomaterial scaffold in tissue engineering research. [http://www.biomateria.com/bio_skin_3.htm 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.

Cosmetic application

Hyaluronan is also now a common skin care ingredient, due to its moisturizing effects. Since 2003 the FDA has approved hyaluronan injections (usually under the trade name Restalyne) for filling soft tissue defects such as facial wrinkles ^*^*. These products are analogous to collagen injections but have the advantages of longer lasting effects and decreased risk of allergic reaction.

Etymology

Hyaluronic acid is derived from hyalos (Greek for vitreous) and uronic acid because it was first isolated from the vitreous humor and possesses a high uronic acid content.

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

Glycosaminoglycans

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