Breakthroughs

December 2002: Saving the Optic Nerve
Matrix Metalloproteinase-9 May Be a Useful Target for Neuroprotective Strategies

Information about what we see is transferred from the eye to the brain via the optic nerve. A tissue with demanding need for oxygen, the optic nerve can be irreversibly damaged by fluctuations in blood flow in a process called ischemia-reperfusion injury. The process underlies many blinding diseases, including glaucoma, which affects a large number of people in the United States and the world. In a paper published in the December 2002 issue of The Journal of Biological Chemistry, Bascom Palmer faculty member M. Elizabeth Fini, Ph.D. and her team report their identification of Matrix Metalloproteinase-9 (MMP-9) as a key participant in optic nerve damage.

Sight begins when specialized retinal neural cells called photoreceptors receive light from the environment and send off a message about what they “see” to the brain. Each contributes a pixel of information to pattern the raw image. This information is then processed as it is passed from neuron-to-neuron until it reaches the innermost retinal layer. There, specialized nerve cells called ganglion cells collect the final data and funnel it through long processes or axons that bundle together in the optic nerve, exiting the back of the eye and projecting into the vision centers in the brain.

Image processing is a tough job and the retinal neural cells require a constant supply of oxygen to feed their metabolic needs. Oxygen is delivered in the blood via the main retinal artery. The artery projects into the eye along the same path as the optic nerve, then branches and re-branches to form a fine network of capillaries called the retinal vasculature. This delivery system ultimately feeds every neural cell. When the system is disrupted, a condition of oxygen starvation or “ischemia” is created and neural cells quickly die. Re-perfusion of the tissue is the only way to halt the carnage. But there is a cost. While essential for life, oxygen is also dangerous. Its rapid return to an ischemic tissue generates destructive molecular species. The cells respond by committing suicide in an effort at damage control. In this way, re-perfusion sets off a second wave of nerve cell death.

To investigate the nature of the cell suicide signal, the research team created ischemic conditions by tying off the optic nerve in an experimental model. Since the retinal artery runs through the nerve, this resulted in its occlusion. When the ligature was released, re-perfusion of the tissue occurred. The team found that this caused loss of inner retinal cells, much as reported by other investigators.

Looking for changes in the tissue that might precipitate cell death, the research team made the novel finding that very specific molecules disappeared from the inner limiting membrane, a key support structure to which the ganglion cells attach their axons. They also observed an increase in an enzyme known to possess the qualities to do this selective job, a member of the Matrix Metalloproteinase (MMP) family called gelatinase B or MMP-9. The findings suggested that MMP-9 might be causal in the observed changes, but did not prove it. The clincher was in subsequent genetic experiments. The team found that disruption of the MMP-9 gene so that its enzymatic product was no longer produced, dramatically protected the retina. Changes to the inner limiting membrane were avoided, neural cell death was limited, and the tissue remained much healthier overall.

“These findings on the key role of MMP-9 parallel those we obtained looking at various types of brain injury in collaboration with Dr. Eng Lo from Harvard Medical School”, says Fini. “Similar findings on brain injury have been made in other labs. The new results show us that there are common mechanisms at play in injury to the retina, which is really just a specialized extension of the brain.”

What might this mean for patients? MMPs are involved in a wide array of pathologies including some big ones like cancer and arthritis. The role of specific MMPs, including MMP-9, in the process of blood vessel growth called “angiogenesis” has stimulated a lot of excitement, since abnormal angiogenesis underlies many diseases. “There is a lot of interest right now in developing MMP inhibitors as drugs”, says Fini. “Every pharmaceutical firm has gotten involved.” In the eye, angiogenesis causes the wet form of macular degeneration, a blinding disease that affects a large number of people as they get older. MMP inhibitors are being looked at as a way to curb this disease. “Now we have a new indication for MMP inhibitors in the eye”, says Fini. “A different sort of change in blood flow, but one that also affects a large number of people, as it appears to contribute to glaucoma. We are excited about following up on this in new studies underway in the lab.”

[back to top]