Sex hormones, proto-oncogene expression and apoptosis: their effects on rheumatoid synovial tissue.
Programmed cell death (apoptosis), is a non-random physiological process characterized by cell fragmentation without leakage of the cellular contents into the extracellular space. Apoptosis is especially important in the immune system. On the other hand the capacity of cells to proliferate and to show local invasiveness, as in cancer cells or the "tumor-like" synoviocytes in rheumatoid arthritis (RA), seems to be controlled by a group of genes called "proto-oncogenes". The early metabolic events in cell apoptosis and proliferation are remarkably similar. The primary location of apoptotic cells in RA synovial tissue is at the level of the synovial lining, varying from rare positive cells to > 50% positive cells. C-jun, c-fos and c-myc oncoproteins seem to be largely restricted to the synovial cells attached to the sites of cartilage and bone destruction. Ovarian follicle atresia could serve as a useful model to study the hormonal regulation of apoptosis in different endocrine tissues. Based on ovarian studies it seems that estrogens generally prevent apoptosis whereas androgens induce apoptosis. The binding of steroids to their receptors forms a complex wherein the receptors are transformed, so that they can then pass through the nuclear membrane and associate with specific recognition sites on DNA. In the majority of cases, the steroid receptors mediate the rapid regulation of the nuclear proto-oncogene transcription. Therefore, they may serve as important "early" regulatory genes and as excellent universal markers in all tissues in steroid hormone action. Since the macrophages are considered to be target cells for sex hormones, we recently evaluated c-myc expression in cytocentrifuge preparations obtained from primary cultures of RA synovial macrophages treated with estrogens, and observed a marked upregulation. Further studies of the influence of sex hormones on synoviocyte apoptosis and proto-oncogene expression should offer new perspectives on the pathogenesis and therapy of synovitis in RA and other rheumatic diseases.