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P53 Gene Linked to Rheumatoid Arthritis

SAN DIEGO, CA -- November 10, 1997 -- Researchers at the University of California-San Diego School of Medicine have found the first gene defects associated with rheumatoid arthritis, a common and debilitating disease affecting one percent of the world’s population.

Mutant p53 genes were found in synovial tissue taken from the joints of patients with severe, chronic rheumatoid arthritis (RA) who were undergoing joint replacement surgery. The research was reported at the American College of Rheumatology national scientific meeting held Nov. 9-12, 1997 in Washington MD.

Defects in the p53 gene are commonly associated with cancer. The normal p53 gene instructs a mildly-damaged cell to repair itself and a severely damaged cell to kill itself. If this gene loses its function, the damaged cell can multiply unchecked, leading to tumor formation. Earlier studies had shown that in severe RA the cells lining the joints, called synoviocytes, had undergone some transformation, appearing more like tumor cells. Scientists believed this process was important to the progression and severity of the disease, but until now did not understand the underlying mechanism.

"We believe the presence of mutated p53 genes in the RA synovium represents a critical step in the progression of the disease," said the study’s lead author Gary Firestein, M.D., professor of medicine in the division of rheumatology, UCSD School of Medicine.

The researchers explained p53 mutations do not cause RA. Rather they are probably the result of intense local chronic inflammation. The faulty genes then are helpless to keep the disease in check and it becomes more aggressive and invasive into the lining of the joint, destroying the cartilage and bone structure.

"This work helps to explain why, even after treating the inflammation, the disease continues its destruction of cartilage and bones,” Firestein said. “This new scientific understanding may lead to new approaches, both in the treatment and prevention of this devastating disease."

While the p53 defects identified in this work were identical to p53 defects associated with cancer, the joint seems to be protected from tumor formation and instead develops a more destructive form of arthritis, according to the researchers.

They also said the mutant genes were found only in joints in the study population -- none were found in participants’ blood or skin cells.

"This means that patients are not born with the mutation; instead, they arise only in the joints during the disease process,” Firestein said. “This suggests that the process that initiates rheumatoid arthritis, such as an attack on the joint tissues by the immune system, might be supplanted by locally damaged cells in later disease."

Additional studies are under way to characterize the activity of these p53 mutations and to determine the functional consequences of p53 suppression in cultured synoviocytes.

This work was also published in the Sept. 30,1997, issue of the Proceedings of the National Academy of Science. The research was supported by grants from the National Institutes of Health.

Thanks to The Doctor's Guide to the Internet™ for the article


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