Mutations in Tumor Suppressor Gene in RA Synovium
Mutations in Tumor Suppressor Gene in RA Synovium
One of Dr. Firestein’s subsequent innovations was his study of genes outside of the immune system that might play a role in the progression of rheumatoid arthritis (RA). Firestein and colleagues at the University of California, San Diego and the La Jolla Institute of Allergy and Immunology started with the knowledge that RA evolves from a local inflammatory disease to a chronic process with both inflammatory and destructive components. They focused on the possibility that the change from a local disease to a chronic process occurs when cells that line the joint (fibroblast-like synoviocytes) achieve independent activation. This means that inflammation could be perpetuated without sustained activation of the immune system.
What Problem Was Studied?
Fibroblast-like synoviocytes exhibit some features reminiscent of transformed cells, meaning that factors in the environment permanently change the function of synoviocytes so that they resemble tumor cells. Experiments performed by Firestein’s group and others showed that synovial cells affected by RA do not undergo as much apoptosis (programmed cell death) as expected. Because the p53 tumor suppressor gene is a key regulator of DNA repair, cell replication, and apoptosis, Firestein and colleagues decided to take a closer look at its function and relation to RA. They hypothesized that alterations in the p53 gene might contribute to the abnormal behavior of RA synoviocytes.
What Was Done in the Study?
To test this hypothesis, the team ran a series of experiments on synovial tissue collected at the time of joint replacement from patients with RA or osteoarthritis (OA). For comparison, healthy synoviocytes from autopsy specimens were obtained and tested as well. Because mutations in the p53 gene had been documented in certain types of tumors, the investigators determined whether similar abnormalities might be present in RA synovium.
What Were the Study Results?
They found that synovial cells from RA patients did indeed have a much higher than expected number of p53 mutations, yet the control cells and those from OA patients did not have excessive p53 mutations.
Inflammation leading to p53 mutations is probably not unique to RA, but might be common to many diseases, says Firestein. An example he gives is ulcerative colitis, which is marked by chronic inflammation, p53 mutations and, ultimately, malignancy. Why p53 mutations in synoviocytes do not lead to malignant tumors in RA is not clear. Dr. Firestein notes that the synovium is “uniquely resistant to malignant transformation.”
What Do These Results Mean to People with RA?
The p53 mutations do not actually cause RA; rather, they are probably the result of intense local inflammation that persists for many years. Dr. Firestein and colleagues proposed that “a burden of mutations accumulates over time and that specific alteration in the p53 gene can contribute to the autonomy of synoviocytes and perpetuation of disease.” Although this concept is controversial, Japanese and French groups subsequently confirmed that p53 mutations can occur in rheumatoid arthritis synovial cells.
Firestein concluded that new therapies targeting synoviocyte transformation might be applicable to arthritis and other inflammatory diseases. “Such approaches might have the advantage of directly addressing tissue destruction and altering the natural history of the disease rather than simply suppressing inflammation.” Specific therapeutic agents designed to target synoviocytes are now in pre-clinical development.
