Role of activin-A and myostatin and their signaling pathway in human myometrial and leiomyoma cell function.

Context: Uterine leiomyomas are highly prevalent benign tumors of pre-menopausal women and the most common indication for hysterectomy. However, the exact etiology of this tumor is not fully understood. Objective: To evaluate the role of activin-A and myostatin, and their signaling pathways in human myometrial and leiomyoma cells. Design: Laboratory study Setting: Myometrial and leiomyoma cells (primary and cell lines) were cultured in vitro. Patients: The study included premenopausal women who were admitted to the hospital for myomectomy or hysterectomy. Interventions: Primary myometrial and leiomyoma cells and/or cell lines were treated with activin-A (4nM) and myostatin (4nM) for different days of interval (to measure proliferation rate) or 30 min (to measure signaling molecules) or 48 h to measure proliferating markers, extracellular matrix mRNA and/or protein expression by real-time polymerase chain reaction (PCR), western blot and/or immunocytochemistry. Results: We found that activin-A and myostatin significantly reduce cell proliferation in primary myometrial cells but not in leiomyoma cells as measured by CyQUANT cell proliferation assay kit. Reduced expression of PCNA and Ki-67 were also observed in myometrial cells in response to activin-A and myostatin treatment. Activin-A also significantly increased mRNA expression of fibronectin, collagen1A1 and versican in primary leiomyoma cells. Finally, we found that activin-A and myostatin activate Smad2/3 signaling but do not affect Erk or p38 signaling in both myometrial and leiomyoma cells. Conclusions: This study results suggest that activin-A and myostatin can exert antiproliferative and/or fibrotic effects on these cell types via Smad2/3 signaling.