CULTURED HUMAN UTERINE SMOOTH-MUSCLE CELLS ARE RETINOID-RESPONSIVE

Primary cultures of human uterine smooth muscle cells have been widely used as a model system to evaluate agents that may play a role in the regulation of both normal and abnormal proliferative responses. We ha ve used this in vitro system to determine if human uterine smooth musc le cells are responsive to treatment with a potent natural derivative of vitamin A, all-trans retinoic acid (ATRA), These studies were also designed to determine if there is a difference in retinoid responsiven ess between normal smooth muscle and adjacent leiomyoma (a benign tumo r of uterine smooth muscle), When cells were cultured in the presence of ATRA, a dose dependent inhibition in proliferation was observed, Th is inhibition in proliferation was accompanied by an alteration in smo oth muscle cell morphology. Both the inhibition in proliferation and t he altered morphology were reversible when ATRA treatment was disconti nued. Responsiveness to retinoids is determined, in part, by the expre ssion of ligand-specific receptors belonging to the steroid/thyroid su perfamily (RARs and RXRs); we have therefore identified the pattern of retinoid receptor transcript expression in human uterine smooth muscl e cells. The data indicate that human uterine smooth muscle cells expr ess retinoic acid receptors RAR alpha, beta, and gamma and retinoid X receptors RXR alpha and beta. No difference in retinoid responsiveness or in the pattern of retinoid receptor expression was observed betwee n normal smooth muscle and adjacent leiomyoma. This is the first obser vation of an antiproliferative effect of ATRA in uterine smooth muscle cells and the first report of retinoid receptor expression patterns i n this cell type, Since retinoids are common pharmacologic tools in th e treatment of a wide variety of hyperproliferative disorders, these o bservations may have both therapeutic and toxicologic implications.