title: Leiomyoma-derived transforming growth factor-β impairs bone morphogenetic protein-2-mediated endometrial receptivity.
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.
  
  
  METHODS
  Experimental.
  
  
  METHODS
  Laboratory.
  
  
  METHODS
  Women with symptomatic leiomyomas.
  
  
  METHODS
  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.
  
  
  METHODS
  Expression of BMP receptor types 1A, 1B, 2, as well as endometrial receptivity mediators HOXA10 and leukemia inhibitory factor (LIF).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Leo F
authors.initials: LF
authors.lastname: Doherty
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut. Electronic address: hugh.taylor@yale.edu.
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Taylor
mesh_terms: D000328:Adult; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D003656:Decidua / Q000187:drug effects / Q000502:physiology; D010064:Embryo Implantation / Q000187:drug effects*; D004717:Endometrium / Q000187:drug effects*; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D011247:Pregnancy; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology*; D014594:Uterine Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D055396:Bone Morphogenetic Protein 2; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2
keywords: Leiomyoma; bone morphogenetic protein; endometrial receptivity; transforming growth factor-β