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Researchers Determine Location of Gene Mutations in Rheumatoid Arthritis

  [ 40 votes ]   [ Discuss This Article ] • August 23, 2002

The precise location and potential mechanism by which mutated genes destroy joints in rheumatoid arthritis patients has been discovered by researchers at the University of California, San Diego (UCSD) School of Medicine.

The findings, reported in the July 23, 2002 issue of the journal Proceedings of the National Academy of Sciences, bring researchers a step closer to understanding joint destruction in rheumatoid arthritis (RA) and developing novel treatments that prevent the crippling progression of the disease.

Investigators used sophisticated micro-dissection techniques on diseased RA tissue to determine the location of mutant p53 genes. They found that the genes are located in island-like clusters in the inner lining of joints called the synovium. Additional tests confirmed that the mutant p53 genes in cell clusters correlated with increased production of immunoregulatory molecules called cytokines in the same region. The release of cytokines by abnormal synovial cells in RA can increase inflammation and tissue destruction in nearby areas of the affected joint.

The studies were conducted by Gary S. Firestein, M.D., professor of medicine and chief of the UCSD Division of Rheumatology, Allergy and Immunology, in collaboration with Douglas Green, Ph.D., La Jolla Institute of Allergy and Immunology, and Nathan Zvaifler, M.D., UCSD Division of Rheumatology, Allergy and Immunology.

The Firestein lab, along with Green and Zvaifler, were the first group to report in 1997 that the p53 gene, perhaps best know for suppressing cancer tumors, also played a role in rheumatoid arthritis.

In recent years, researchers have investigated features that are similar between cancer and rheumatoid arthritis. For example, because of the way it destroys cartilage and bone, rheumatoid arthritis has been described by some as a locally invasive, tumor-like inflammatory process that involves the joints.

Affecting approximately 1 percent of the world's population and more than 2 million Americans, rheumatoid arthritis is characterized by inflammation of the joint lining. This inflammatory tissue can invade and damage bone and cartilage as cells release enzymes that destroy these tissues, resulting in misalignment, pain, loss of movement, and, in severe cases, requiring joint replacement surgery. The cause of rheumatoid arthritis is not known.

"The mutations in the p53 gene do not cause rheumatoid arthritis," Firestein said. "The mutations are caused by RA, especially the production of toxic molecules produced by inflammatory cells. Then, the mutations enhance the destructive course of the disease, making it much worse."

Specifically, the degree of inflammation is so intense in rheumatoid arthritis patients that neutrophils and other inflammatory cells are attracted to the site. These cells normally produce toxic molecules designed to kill invading bacteria and other pathogens as a host defense mechanism. In this case however, the molecules attack normal tissue over a period of years and can eventually alter the normal p53 genes. In turn, small clusters of mutated cells proliferate, thereby producing islands within the joint lining, much like freckles that can occur in skin damaged after exposure to ultraviolet light from the sun.

The researchers found the location of mutated p53 genes by taking synovial tissue samples from joint-replacement patients who had been diagnosed with severe rheumatoid arthritis. The tissue samples were frozen, then finely dissected into tiny sections that could be examined under high-power microscopes. The individual regions were then analyzed for the presence of mutations to determine the size and location of the mutant islands.

Next, the investigators looked for correlations between p53 mutations and cytokine expression. They found that regions of synovial tissue with high p53 mutation rates contained approximately four times more cytokine than tissue without p53 mutations. The authors said this indicates that one function of normal p53 is to inhibit over-expression of cytokines and assist in the resolution of inflammation.

Now that p53 location and function have been determined, the investigators are studying the evolution of rheumatoid arthritis to learn if mutations occur early or later in disease progression.

"This will help us determine the window of opportunity for preventing the severe destruction caused by rheumatoid arthritis," Firestein said.

The p53 research was supported by grants from the National Institutes of Health. Additional authors of the PNAS paper were first author Yuji Yamanishi, M.D., Ph.D., and David L. Boyle, Sanna Rosengren, Ph.D., UCSD Division of Rheumatology, Allergy and Immunology.

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