A specific signal in the brain and spinal cord prevents tissue damaged in that part of the body when multiple sclerosis strikes from repairing itself afterwards. That's the conclusion of a group of scientists who claim they've unraveled the underlying reasons behind the permanence of MS-inflicted damage, which also might eventually lead to medicines to fix it.¹

"For many years, scientists have understood that damage to the insulation-like sheath surrounding nerve cells in the brain, called myelin, is part of the disease process for MS and other brain disorders," said Larry Sherman, PhD, a neuroscientist at Oregon Health and Science University, who headed this study. "In recent years, it became clear that there were cells at the sites of this damage that should have the capacity to repair the brain and spinal cord, but they fail to do so."

Myelin is a fatty substance that surrounds and protects nerve endings in the central nervous system, which encompasses the brain and spinal cord. It's believed that MS involves an abnormal attack against myelin by the body's immune system. Normally, immune cells seek out and destroy foreign disease-causing organisms, but in the case of MS, the immune system apparently has a new, aberrant, function. When myelin is damaged or destroyed, the nerve endings it normally protects can no longer communicate with each other, and the result is the symptoms that are associated with the disease.²

Unexpected Turn of Events
Sherman and a team of neurologists at Oregon Health and Science University collaborated on the research following an unrelated animal study evaluating tumors in the central nervous system. In the previous studies, mice had been bred to overproduce a protein that experts believed played a part in tumor formation. But instead of developing tumors, the protein, called CD44, caused tremors in the mice similar to what's seen in people with MS.

When the investigators looked further, they found that the tremors were linked to the loss of myelin on the mice's nerve cells, just like the myelin damage that's seen in MS. They also found high amounts of a neurological carbohydrate known as hyaluronic acid (HA) in the brains of the animals.

"We were very surprised," Sherman said. "Instead of getting tumors, they got tremors." In fact, these mice were remarkably similar in terms of their myelin damage as what had been seen in mice used in studies of MS pathology, he said.

That set the latest study into motion. Based on what they had learned, Sherman and his colleagues wanted to find out if hyaluronic acid has a major role in keeping damaged myelin that occurs in MS from being repaired. They examined tissue from people with MS, and found very high amounts of HA. "That's when it all hit us that maybe we were on to something," Sherman told Priority Healthcare.

Blocking Myelin Repair
"These investigations revealed that oligodendrocytes [oh-lih-goh-DEN-droh-sites], which are cells that form myelin in the brain, were prevented from repairing the damaged myelin when there were elevated levels of HA," explained study investigator Bruce Bebo, PhD, an associate professor of Neurology at OHSU. "By studying another mouse model in my lab, we made the connection between heightened levels of HA … and myelin loss in an MS-like disease in mice."

In fact, before this discovery, it was known that oligodendrocyte parent cells in the brain fail to mature into working oligodendrocytes, which would then re-form myelin after the damage occurred in MS, Sherman explained. But this is the first time it was discovered that hyaluronic acid is responsible.

The cells that manufacture hyaluronic acid were also identified, and it was found that the higher levels of HA were, in turn, boosting levels of the CD44 protein, Bebo stated.

Confirming Their Discovery
To further understand the significance of these substances in the progression of MS, the researchers examined tissue samples of immature rat oligodendrocytes. When they applied hyaluronic acid to the tissue samples, the carbohydrate kept the myelin-making cells from maturing. They then wanted to test this process in an animal. When they injected HA into a group of animals that had damaged myelin, the damage was never repaired. However, when they reduced levels of HA, myelin then began forming.

"We have this real sense that, in fact, hyaluronic acid, which clearly builds up in MS patient lesions and in every model of MS that we've looked at so far, has this rather potent ability to prevent remyelination, and we think it's doing it because of this capacity to prevent the oligodendrocytes from maturing," explained Sherman.

The New Question: Why?
The next step is understanding why hyaluronic acid prevents oligodendrocyte precursors, or parent cells, from maturing and making myelin after it's been damaged by disease. The National MS Society has awarded Sherman and his colleagues a grant to study this very question, he said. "We're just getting those studies underway."

What does all this molecular research mean for people with MS? Understanding how the CD44 protein and hyaluronic acid mediate the progress of the disease could lead to ways to block their activity. Blocking their activity, in turn, could help myelin-making cells replenish the central nervous system with new myelin after it's been damaged.

"It is our hope that we can interfere with this disease process at one or multiple stages," said Stephen Back, MD, PhD, a study investigator and associate professor of Pediatrics and Neurology at OHSU. "Of course, for those already battling a myelin-destroying disease, you would want to try and promote the return of myelin-forming cells."

Not only does this discovery help pave the way toward possible ways to prevent the progression of MS and other neurological diseases, but it might also lead to ways to repair damaged myelin, added Sherman.

"The other big question is, could you break down this hyaluronic acid in a real demyelinated lesion and actually promote remyelination?" Sherman asked. "That's the next big question in regard to developing a therapeutic approach."

1. Back SA, Tuohy TM, Chen H et al. Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat Med 2005 Aug 7;[Epub ahead of print].
2. National Multiple Sclerosis Society. What is Multiple Sclerosis? Available at: http://www.nationalmssociety.org/What%20is%20MS.asp. Accessed August 5, 2005.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.