Hyaluronan

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Hyaluronan (also called hyaluronic acid or hyaluronate) is a non-sulfated 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. The average 70kg man has roughly 15 grams of hyaluronan in his body, one third of which is turned over (degraded and synthesised) every day.^[1]

Hyaluronan

1 Functions
2 Structure
3 Synthesis
4 Degradation
5 Medical applications
6 Cosmetic application
7 Etymology
8 As seen on ABC's 20/20
9 References
10 External links

[edit] Functions

Until the late 1970s, hyaluronan was described as a "goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix. For example, hyaluronan is a major component of the synovial fluid and was found to increase the viscosity of the fluid. Along with lubricin, it is one of the fluid's main lubricating components.

Hyaluronan is an important component of articular cartilage, where it is present as a coat around each cell (chondrocyte). When aggrecan monomers bind to hyaluronan in the presence of link protein, large highly negatively charged aggregates form. These aggregates imbibe water and are responsible for the resilience of cartilage (its resistance to compression). The molecular weight (size) of hyaluronan in cartilage decreases with age however the amount increases.^[2]

Hyaluronan is also a major component of skin, where it is involved in tissue repair. When skin is excessively exposed to UVB rays, it becomes inflamed (sunburn) and the cells in the dermis stop producing as much hyaluronan and increase the rate of its degradation. Hyaluronan degradation products also accumulate in the skin after UV exposure.^[3]

While it is abundant 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, 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 participates in cell adhesion interactions required by tumor cells.

Although hyaluronan binds to CD44, there are evidence to support that hyaluronan degradation products transduce their inflammatory signal through Toll-like receptor 2 (TLR2), TLR4 or both TLR2 and TLR4 in macrophages and dendritic cells. TLR and hyaluronan play a role in innate immunity.

[edit] 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 β-1,4 and β-1,3 glycosidic bonds. Hyaluronan can be 25,000 disaccharide repeats in length. Polymers of hyaluronan can range in size from 5,000 to 20,000,000 Da in vivo. The average molecular weight in human synovial fluid is 3−4 million Da and hyaluronan purified from human umbilical cord is 3,140,000 Da.^[4]

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.

[edit] 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 as it is extruded through the cell membrane into the extracellular space.

[edit] 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. In addition, recent studies showed that hyaluronan fragments, not native high molecular mass of hyaluronan, can induce inflammatory responses in macrophages and dendritic cells in tissue injury and in skin transplant rejection.

[edit] 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 eye surgery (i.e. corneal transplantation, cataract surgery, glaucoma surgery and surgery to repair retinal detachment) ^[5]. Other biomedical companies also produce brands of hyaluronan for ophthalmic surgery ^[6]^[7].

Hyaluronan is also used to treat osteoarthritis of the knee ^[8]^[9]^[10]. 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 ^[11]^[12] have cast doubt on the efficacy of hyaluronan injections and hyaluronan is recommended primarily as a last alternative to surgery. Oral use of Hyaluronan has been lately suggested although effectiveness needs to be demonstrated. Some preliminary clinical studies exist that suggest that oral administration of Hyaluronan has a positive effect on osteoarthritis.

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. ^[13]^[14]

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.

[edit] Cosmetic application

Hyaluronan is a common ingredient in skin care products.

In 2003 the FDA has approved hyaluronan injections for filling soft tissue defects such as facial wrinkles. Restylane is a common trade name for the product. Hyaluronan injections temporarily smooth wrinkles by adding volume under the skin, with effects typically lasting for six months. People who have been on any blood medication with in the last five years should not inject this drug until the five year span is over. This drug is also not good for the elderly because it can cause memory loss.

[edit] 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 anand typically exists in vivo in its polyanionic form, it is most commonly referred to as hyaluronan.

[edit] As seen on ABC's 20/20

A November 2002 story on ABC’s 20/20 covered “The Village of Long Life”, a Japanese village called Yazuri Hara about two hours from Tokyo where 10% of the population is 85 years or older. Some scientists believe that the resident’s unusual diet of predominantly sticky starches (like sweet potatoes), stimulates the production of hyaluronic acid, which helps to support healthy skin, eyesight and joint function and keeps them feeling youthful well into their later years. You can buy hyaluronic pads for your face