Leiomyoma derived transforming growth factor β impairs bone morphogenetic protein 2 mediated endometrial receptivity

Capsule:
Fibroid-derived TGF-b3 alters endometrial BMP-2 signaling and prevents up-regulation of HOXA10 and leukemia inhibitory factor. The TGF-b blockade restoresBMP-2 stimulation ofHOXA10 and leukemia inhibitory factor andmay improve endometrial receptivity.

Authors:
Leo F. Doherty, M.D., Hugh S. Taylor, M.D.

Volume 103, Issue 3, Pages 845-852

Abstract:

Objective:
To determine whether transforming growth factor (TGF)-β3 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-β was blocked by two approaches: TGF-β pan-specific antibody or transfection with a mutant TGF-β 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-β 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-β 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-β antibody or transfection with mutant TGF receptor prevented HOXA10 and LIF repression.

Conclusion(s):
Leiomyoma-derived TGF-β was necessary and sufficient to alter endometrial BMP-2 responsiveness. Blockade of TGF-β 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.

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