Abstract
BackgroundAdenomyosis is a medical condition defined by the abnormal presence of endometrial tissue within the myometrium, in which fibrosis occurs with new collagen deposition and myofibroblast differentiation. In this study, the effect of several mediators and growth factors on collagen expression was investigated on human endometrial stromal cells (fibroblasts) derived from adenomyotic endometrium.Experimental approachRT-PCR, Western blot analysis, pharmacological interventions and siRNA interference were applied to primary cultured human endometrial stromal cells (fibroblasts). Immunohistochemistry was used to analyze protein expression in adenomyotic endometrium tissue specimens.ResultsOf the tested mediators, transforming growth factor β1 (TGFβ1) and its isoforms were effective to induce collagen and connective tissue growth factor (CTGF) expression. Collagen and CTGF induction by TGFβ1 could be reduced by the inhibitors targeting DNA transcription, protein translation, and Smad2/3 signaling. Interestingly, TGFβ1 induced Smad2/3 phosphorylation and CTGF mRNA expression, but not collagen mRNA expression, suggesting that TGFβ1 mediates collagen expression through CTGF induction and Smad2/3 activation. In parallel, TGFβ1 and CTGF also induced expression of heat shock protein (HSP) 47, a protein required for the synthesis of several types of collagens. However, only CTGF siRNA knockdown, could compromise TGFβ1-induced collagen expression. Finally, the immunohistochemistry revealed vimentin- and α-SMA-positive staining for (myo)fibroblasts, TGFβ1, collagen, and CTGF in the subepithelial stroma region of human adenomyotic endometria.Conclusion and implicationsWe reveal here that TGFβ1, collagen, and CTGF are expressed in the stroma of adenomyotic endometria and demonstrate that TGFβ1 can induce collagen production in endometrium-derived fibroblasts through cellular Smad2/3-dependent signaling pathway and CTGF expression, suggesting that endometrial TGFβ may take part in the pathogenesis of adenomyosis and ectopic endometrium may participate in uterine adenomyosis.
Highlights
Uterine adenomyosis is a medical condition defined by the abnormal presence of endometrial tissue within the myometrium and the main mechanisms include sex hormone aberrations, inflammation and neuroangiogenesis, proliferation and fibrosis [1]
transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF) induced expression of heat shock protein (HSP) 47, a protein required for the synthesis of several types of collagens
We reveal here that TGFβ1, collagen, and CTGF are expressed in the stroma of adenomyotic endometria and demonstrate that TGFβ1 can induce collagen production in endometrium-derived fibroblasts through cellular Smad2/3-dependent signaling pathway and CTGF expression, suggesting that endometrial transforming growth factor β (TGFβ) may take part in the pathogenesis of adenomyosis and ectopic endometrium may participate in uterine adenomyosis
Summary
Uterine adenomyosis is a medical condition defined by the abnormal presence of endometrial tissue within the myometrium and the main mechanisms include sex hormone aberrations, inflammation and neuroangiogenesis, proliferation and fibrosis [1]. Fibrosis includes the activation of stromal fibroblasts within connective tissue, namely myofibroblasts with expression of α-smooth muscle actin (α-SMA). The formation of fibrosis correlates with extracellular matrix (ECM) production, new collagen deposition, and transforming growth factor β (TGFβ)-induced myofibroblast differentiation [5, 6]. Adenomyosis is a medical condition defined by the abnormal presence of endometrial tissue within the myometrium, in which fibrosis occurs with new collagen deposition and myofibroblast differentiation. The effect of several mediators and growth factors on collagen expression was investigated on human endometrial stromal cells (fibroblasts) derived from adenomyotic endometrium. Immunohistochemistry was used to analyze protein expression in adenomyotic endometrium tissue specimens
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