On the Role of Hyaluronan in Aging and POAG

Glaucoma is one of the four major causes of blindness and vision disability. In its most common form, primary open angle glaucoma, it is an insidious theft of sight. Typically there are no symptoms and a person is unaware of their disease. Although many individuals have family members who are affected, as a rule there are no clues to the disease nor are there helpful predictive risk factors for an individual who has the disease. An ophthalmologist makes the diagnosis of primary open angle glaucoma by: 1) an increase in intraocular pressure (normal pressure is 12 to 21 mmhg), 2) the appearance of the anterior chamber angle (which is formed by the junction of the iris, sclera, cornea) is open when examined by a special contact lens, and 3) loss of optic nerve fibers which result in a characteristic pallor of the optic nerve with associated loss of peripheral and then central vision. The cause of glaucoma is unknown. It is estimated that two in a thousand people of age 40-49 have the disease and 20-30 in a thousand people of age 70 have the disease. The most likely cause of the disease is a change in the filter–the trabecular meshwork– which allows fluid to exit the eye. The filter is complex and in many respects self regulating. The cells which make the filter have a genetic timetable and are influenced by the outside, ie. extracellular signals. All cells are preset with a timetable that determines their activity. The outside of a cell is within a complex matrix which contains many components. One component which appears to be critical to the function of trabecular meshwork is hyaluronic acid. Hyaluronic acid is composed of two repeating sugars, glucosamine and glucuronic acid, which form a network. Our laboratory has studied hyaluronic acid for many years and has reported that hyaluronic acid decreases in the trabecular meshwork with patients that have primary open angle glaucoma. In addition, hyaluronic acid decreases within the support framework of the optic nerve, the lamina cribrosa. The amount of any substance in a biological system is controlled by its receptor. The lifespan of a red blood cell, for example, is signaled by the surface of the cell and receptors which pick it up and remove it. It is likely, therefore that the receptor on trabecular meshwork cells controls the amount of hyaluronic acid. In the most dramatic example of premature aging, a rare disease called progeria causes a seven year old child to assume the appearance of a seventy year old person. Constant loss of hyaluronic acid occurs in children with progeria. As a person ages it may be that hyaluronic acid is lost from the trabecular meshwork. Exactly why hyaluronic acid decreases or is absent in the trabecular meshwork and the lamina cribrosa is a specific aim of our grant application to the American Health Assistance Foundation. In preliminary studies, we have found out that the receptor for hyaluronic acid, CD44, is present in human trabecular meshwork. The amount of CD44 increases with age. It is known that CD44 is a highly specific cell product. The gene of CD44 is on chromosome 11, contains 19 exons (an exon is the part of the gene which is used) and exon2-exon10 are variant (that is, may or may not be expressed by alternative splicing). Thus CD44 can have many forms and presumably many functions. The enzyme complex which makes hyaluronic acid is totally unique. The enzyme complex, hyaluronic acid synthase, consists of two protein parts and they are present in the cell membrane. Almost all other cell product are made inside the cell and then utilized internally or transported outside the cell. The unique position of hyaluronic acid enzymes permit the newly formed hyaluronic acid to be immediately delivered to the outside of the cell. We recently identified the hyaluronic acid synthetase in human trabecular meshwork. In this proposal, we plan to determine whether the enzyme complex is present in primary open angle glaucoma. We plan to study the HAS enzyme which makes hylauronic acid and to study CD44 receptor which controls the activity of hyaluronic acid. These two approaches of understanding why hyaluronic acid decreases with age and particularly in primary open angle glaucoma, are the classic approach. If the control of synthesis and of removal of hyaluronic acid are known, its function is easier to understand. The long term goal of the project is to study the activation of CD44 and HA synthesis to find out whether the activities of the receptor can be modified by potential new drugs and to, perhaps, deliver genetic information to revitalize the intrinsic timetable of a cell. Although, ophthalmologists have many pharmacological tools, laser treatments, and surgical procedures, the individual with glaucoma will lose significant vision and all patients are faced with the daily confrontation of potential loss of vision. In our view, to change the filter is a more direct treatment modality rather than to attempt to decrease fluid production, increase fluid removal or to create surgical bypass of fluid, which tries to correct the damage after it has already been done. Treating the filter in the first place would be the practical thing to do.