Society-supported researchers have reported that an immune-system protein known as “osteopontin” appears to play a crucial role in the immune attack in MS and its progression, and may be a potential target for developing therapies to treat the disease. Lawrence Steinman, MD (Stanford University, California), Jorge Oksenberg, PhD (University of California at San Francisco) and colleagues published their findings in the November 23, 2001 issue of Science. This study was supported in part by grants and fellowships from the National MS Society.

Background:

In MS, immune system attacks are launched against myelin (the substance that insulates nerve fibers) and nerve fibers in the brain and spinal cord. The cause and mechanisms that underlie these attacks are not known. Also unknown is why MS often involves progressive disability: Although most people with MS start out with relapsing-remitting disease (characterized by partial or total recovery after attacks), many later develop a steadily progressive disability, or experience progression from the onset. Dr. Steinman and colleagues set out to determine what immune messenger proteins might be involved in the development and progression of MS by examining tissue from individuals with MS and by exploring activity of these proteins in rodents with MS-like disease.

Study:

The investigators sought to identify immune proteins involved in the development of EAE, an MS-like disease, in rats. They used “microarray,” also known as “gene chip” technology, which can identify hundreds of active genes at once. Because genes encode instructions for the manufacture of specific proteins, determining which genes are active provides clues to which proteins are influencing the disease process. The investigators also determined which genes were inactive in rats that had been treated to protect them from developing EAE. The microarray test showed that genes for the immune protein known as osteopontin were elevated in active EAE, and remained at normal levels in rats protected from the disease. Osteopontin is of particular interest because it is known to play a role in enhancing inflammation.

The team performed similar genetic screens on brain tissue from people with MS and from people who did not have the disease.  In these studies as well, osteopontin was one of several genes found prominently in MS tissue, compared with controls. Osteopontin was present in immune and nerve cells in areas of myelin damage.

The investigators went on to study the effects of osteopontin on the course of EAE in mice. They found that the protein was very active in areas of myelin damage, both during relapse and remission, and both in myelin-making cells and in nerve cells. In mice that were genetically engineered to lack osteopontin, the progression of EAE was inhibited, and the severity of disease significantly reduced.

Conclusion:

The authors conclude that the immune protein osteopontin may play several roles in increasing inflammation in the central nervous system in EAE, an animal model for MS, and is present in the brains of individuals with MS.  In EAE, osteopontin may play a role in determining severity of disease and progression.  Thus, osteopontin may present a target for developing therapies that block the progression of EAE and perhaps MS as well. These laboratory findings present an exciting opportunity for future study. However, more research is required to determine the exact roles of this protein, as well as the therapeutic possibilities it presents.

Research Programs Department