Leiomyoma-derived transforming growth factor-ß impairs bone morphogenetic protein-2-mediated endometrial receptivity.

ABSTRACT

OBJECTIVE: To determine whether transforming growth factor (TGF)-ß3 is a paracrine signal secreted by leiomyoma that inhibits bone morphogenetic protein (BMP)-mediated endometrial receptivity and decidualization. DESIGN: Experimental. SETTING: Laboratory. PATIENT(S) Women with symptomatic leiomyomas. INTERVENTION(S) Endometrial stromal cells (ESCs) and leiomyoma cells were isolated from surgical specimens. Leiomyoma-conditioned media (LCM) was applied to cultured ESC. The TGF-ß was blocked by two approaches TGF-ß pan-specific antibody or transfection with a mutant TGF-ß receptor type II. Cells were then treated with recombinant human BMP-2 to assess BMP responsiveness. MAIN OUTCOME MEASURE(S) Expression of BMP receptor types 1A, 1B, 2, as well as endometrial receptivity mediators HOXA10 and leukemia inhibitory factor (LIF). RESULT(S) Enzyme-linked immunosorbent assay showed elevated TGF-ß levels in LCM. LCM treatment of ESC reduced expression of BMP receptor types 1B and 2 to approximately 60% of pretreatment levels. Preincubation of LCM with TGF-ß neutralizing antibody or mutant TGF receptor, but not respective controls, prevented repression of BMP receptors. HOXA10 and LIF expression was repressed in recombinant human BMP-2 treated, LCM exposed ESC. Pretreatment of LCM with TGF-ß antibody or transfection with mutant TGF receptor prevented HOXA10 and LIF repression. CONCLUSION(S) Leiomyoma-derived TGF-ß was necessary and sufficient to alter endometrial BMP-2 responsiveness. Blockade of TGF-ß prevents repression of BMP-2 receptors and restores BMP-2-stimulated expression of HOXA10 and LIF. Blockade of TGF signaling is a potential strategy to improve infertility and pregnancy loss associated with uterine leiomyoma.