Hyaluronan (HA) also known as hyaluronic acid, hyaluronate and mucin is a polysaccharide composed of repeating disaccharides of glucuronic acid and N-acetylglucosamine. Hence hyaluronan belongs to the family of glycosaminoglycans. An HA molecule can be made up of hundreds to thousands of these repeat sugar units. HA tends to maintain the status of a viscoelastic solution or paste depending on the concentration and size of the molecules. These long molecules tend to aggregate into mesh works. In solution HA molecules assume a complex ribbon coil structure. A good analogy would be Jell-O®. When Jell-O® is diluted with too much water it is very soft and runny. If not enough water is added it becomes almost a solid. In like manner when HA molecules are in low concentration or of smaller size molecules they form a thick fluid; and when present in high concentration or longer size molecules they form a paste or semisolid substance. Thus HA has a very important structural function in the body and varies in consistency from a thicker tenacious fluid such as seen in joint fluid or in the skin of Shar-Pei (recall how “sticky” the fluid is in a skin laceration in the Shar-Pei) to a solid-type material as is seen in joint cartilage. Due to its structure HA also facilitates cell shape changes and movement of cells due to its role in the pericellular envelope which surrounds cells. The HA molecules are constantly changing their orientation much as a spring does.
HA is degraded by enzymes called hyaluronidases. Degradation normally occurs when HA enters the afferent lymph and is transported to the local lymph nodes. Oddly enough Streptococcus bacteria produce hyaluronidase which may be a factor in the development of Streptococcal Toxic Shock Syndrome in the breed. When HA is degraded or broken down it tends to produce fragments of different sizes. Smaller fragments of HA stimulate angiogenesis (formation of blood vessels) and stimulate inflammatory responses such as up-regulation of cytokines, chemokines and adhesion molecules – these are all bad things. These smaller fragments signal the production of IL-1, TNF-a, IGF-1 and iNOS by macrophages which are pro-inflammatory substances as well. Larger fragments tend to promote cell stability and integrity, are anti-inflammatory and immunosuppressive.
HA interacts with cell surface receptors such as CD44, LYVE-1 (Lymphocytic endothelial hyaluronan receptor), RHAMM (Receptor for Hyaluronan-Mediated Motility) and many others. CD44 is the major HA cell surface receptor. It mediates cellular events involved in cell growth and differentiation. It is also a primary mediator of the uptake and degradation of HA in many cells. It has important functions in cell migration during morphogenesis, angiogenesis, tumor invasion and metastasis. LYVE-1 is an HA receptor confined to the lymphatic vessels and sinuses which are the main sites of HA degradation. RHAMM seems to play a role in cellular responses to injury, chronic inflammation and cellular transformation as occurs in cancer states.
Possible areas of research for hyaluronan:
- Inflammatory Bowel Disease – HA levels are increased in the gastrointestinal tract of IBD patients. This correlates with increases in CD44 levels as well.
- HA and HA receptors seem to have a major role in the growth and spread of several tumor types.
- HA and HA receptors play a major role in wound healing in the skin.
- In the embryo HA serves as a “mold” for fetal cells to migrate into and differentiate into various organs and other structures.
- The role of HA and its degradation products in the inflammatory response. This area may allow development of pharmaceuticals to control or block inflammation.
Specific areas for potential research in the Shar-Pei might include:
- Streptococcal hyaluronidases and their potential role in Streptococcal Toxic Shock Syndrome in the breed.
- The aggressiveness of mast cell cancer in the breed.
- Possible role of HA and Swollen Hock Syndrome, Swollen Carpus Syndrome and Swollen Muzzle Syndrome in FSF.
In The Journal of Pediatrics, Volume 136, Number 1, 2000 an article appeared, A new disorder of hyaluronan metabolism associated with generalized folding and thickening of the skin by Ramsden CA, Bankier A, Brown TJ, Cowen PSJ, Frost GI, McCallum DD, Studdert VP and Fraser JR. This was a case report of an infant born with excessive skin folding, plates and peau d’orange skin which the authors realized was very similar to the appearance of the Chinese Shar-Pei breed. The course of the case was discussed and the primary abnormality found was excessively high levels of serum hyaluronan. As the child is growing the skin condition is resolving quite a bit. The important part of this article for us was the study the authors did on Shar-Pei in which they measured plasma hyaluronan levels and found they were about 5 times normal for dogs of other breeds. In the child the disorder was thought to result from abnormal control of hyaluronan synthesis and this may be the mechanism responsible for the Shar-Pei phenotype as well. Skin biopsies of the child and a Shar-Pei showed large amounts of hyaluronan in the dermis of the skin. It is known that the largest amounts of hyaluronan in humans are found in the skin. The implication of the article is that there is a genetic defect responsible for the condition in this child and a similar defect may exist in the Shar-Pei breed.
An excellent web site with articles on hyaluronan can be found at GlycoForum/GlycoSquare, http://www.glycoforum.gr.jp/science/hyaluronan.