transforming-growth-factor-beta and Adenomyosis

Adenomyosis is a common gynecologic disorder defined by the presence of endometrial glands and stroma within the uterine myometrium. This review focusses on: (1) current understanding of cellular and molecular mechanisms of adenomyosis-related fibrogenesis, (2) transforming growth factor beta (TGF-β)-dependent or TGF-β-independent mediators of fibrogenesis, and (3) the origin of fibrogenic myofibroblasts. We collected a literature search from PubMed and EMBASE database up to December 2018. First, causative factors of adenomyosis are classified into exogenous traumatic damage (surgical interventions, including curettage, normal delivery, or cesarean section) and endogenous traumatic damage (mechanical strain or myometrial hyperperistalsis). The mechanical forces and injury (microdehiscences) are fundamental regulators of cell behavior and central to our understanding of disease pathogenesis. Adenomyosis is characterized by abnormal response to injury and activation of myofibroblasts in the myometrium through altered barrier function of the endometrial-myometrial junctional zone (EMJZ). Second, we summarize recent advances on the molecular mechanism of fibrosis. Two distinct populations of myofibroblasts, highly myogenic cells, and nonmyogenic cells arise possibly through the TGF-β-dependent and TGF-β-independent processes. TGF-β-independent mechanisms are still intriguing and far from clear. Third, the importance and implications of resident fibroblasts, bone-marrow stem cells-derived fibrocytes, and epithelial-mesenchymal transition-derived myofibroblasts in fibrosis remain uncertain. Finally, originally adenomyosis was believed to be the single entity, but this disorder is composed of multiple heterogeneous subtypes. Key mediators of fibrogenesis may vary widely and largely depend on adenomyosis subtype. In conclusion, both cyclic mechanical strain and EMJZ weakness (microdehiscences) may be a prerequisite for adenomyosis fibrogenesis through the mechanotransduction process. Since there are significant molecular variations among affected individuals, the approach to identify key mediators of fibrosis remains challenging.

Topics: Adenomyosis; Delivery, Obstetric; Endometrium; Female; Fibroblasts; Fibrosis; Humans; Mechanotransduction, Cellular; Myofibroblasts; Myometrium; Pregnancy; Transforming Growth Factor beta

To determine whether there is a correlation between stiffness measured by strain elastography and the severity of dysmenorrhea and to determine the value of elastography in evaluating severe dysmenorrhea in patients with adenomyosis.. The correlation between tissue stiffness and dysmenorrhea was analyzed by performing elastography on premenopausal women diagnosed with adenomyosis. Expression levels of transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA), and protein gene product 9.5 (PGP9.5) were detected by immunohistochemistry; the correlation of TGF-β and α-SMA levels with the tissue stiffness and the degree of fibrosis was further analyzed. Also, the relationship of the PGP9.5 expression level with the tissue stiffness and degree of dysmenorrhea was determined.. The degree of dysmenorrhea was significantly positively correlated with lesion stiffness in patients with adenomyosis but not with the uterine or lesion volume. The cutoff for the strain ratio was > 1.36 between the adenomyosis and control groups, with an area under the curve (AUC) of 0.987. For severe dysmenorrhea, the cutoff for the strain ratio was > 1.65 in patients with adenomyosis, with an AUC of 0.849. TGF-β, α-SMA, and PGP9.5 expression levels were higher in adenomyotic lesions than in the endometrium of the adenomyosis and control groups. Both TGF-β and α-SMA levels were positively correlated with the tissue stiffness and degree of fibrosis. Additionally, the expression level of PGP9.5 showed a positive correlation with the tissue stiffness and degree of dysmenorrhea.. Elastography can be used to evaluate the degree of dysmenorrhea; the greater the tissue stiffness, the greater the degree of dysmenorrhea. In addition, elastography performed well in the diagnosis of adenomyosis and the evaluation of severe dysmenorrhea in patients with adenomyosis.

Topics: Adenomyosis; Dysmenorrhea; Elasticity Imaging Techniques; Female; Fibrosis; Humans; Transforming Growth Factor beta

Adenomyosis is defined as the presence of ectopic nests of endometrial glands and stroma within the myometrium. Adenomyosis is a common cause of dysmenorrhea, menorrhagia, and chronic pelvic pain but is often underdiagnosed. Despite its prevalence and severity of symptoms, its pathogenesis and etiology are poorly understood. Our previous study showed that aberrant activation of β-catenin results in adenomyosis through epithelial-mesenchymal transition. Using transcriptomic and ChIP-seq analysis, we identified activation of TGF-β signaling in the uteri of mutant mice that expressed dominant stabilized β-catenin in the uterus. There was a strong positive correlation between β-catenin and TGF-β2 proteins in women with adenomyosis. Furthermore, treatment with pirfenidone, a TGF-β inhibitor, increased E-cadherin expression and reduced cell invasiveness in Ishikawa cells with nuclear β-catenin. Our results suggest that β-catenin activates TGF-β-induced epithelial-mesenchymal transition in adenomyosis. This finding describes the molecular pathogenesis of adenomyosis and the use of TGF-β as a potential therapeutic target for adenomyosis.

Topics: Adenomyosis; Animals; beta Catenin; Binding Sites; Cadherins; Disease Models, Animal; Disease Susceptibility; Epithelial-Mesenchymal Transition; Fluorescent Antibody Technique; Gene Expression Regulation; Humans; Immunohistochemistry; Mice; Mice, Transgenic; Protein Binding; Transforming Growth Factor beta

Adenomyosis is a common chronic gynecological disorder with some tumor-like properties, including aberrant proliferation, invasion and migration. Berberine (BBR) is an isoquinoline derivative alkaloid with diverse pharmacological activities for the treatment of a wide variety of diseases. However, the effect of BBR on adenomyosis has not been understood. This study was to evaluate the potential therapeutic effect of BBR on ectopic endometrial stromal cells (EESCs) isolated from patients with adenomyosis. Our data showed that BBR significantly inhibited the proliferation and viability of eutopic endometrial stromal cells (EuESCs) and EESCs, while slightly affected the growth of normal endometrial stromal cells (NESCs). BBR markedly exhibited a growth inhibitory effect on EESCs by triggering apoptosis and cell cycle arrest, and alleviating the expression of inflammatory invasive phenotypes (IL-6, IL-8, TGF-β, EGF, VEGF, and MMP2). The alleviation of inflammatory invasive phenotypes partly involved nuclear translocation of NFκB/p65 and stat3 activation. Taken together, BBR markedly inhibits the growth of EESCs and might be a promising new strategy for the treatment of adenomyosis.

Topics: Adenomyosis; Adult; Apoptosis; Berberine; Cell Cycle; Cell Proliferation; Cells, Cultured; Endometrium; Epidermal Growth Factor; Female; Humans; Interleukin-6; Interleukin-8; NF-kappa B; Phenotype; STAT3 Transcription Factor; Stromal Cells; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Young Adult

To estimate the phenotypic characterization of fibrotic process in adenomyosis occurring at the inner or the outer myometrium.. Eight cases of adenomyosis occurring at the inner myometrium (Subtype I) and 10 cases of adenomyosis occurring at the outer myometrium (Subtype II), and 10 normal counterparts were used in this study. A immunohistochemical study for smooth muscle cells (SMCs) was performed using cytoskeletal proteins, Type I and III collagen, TGF-β and its signaling molecules.. An increased expression of Type I collagen was observed in the extracellular matrix of adenomyotic foci. In normal uteri, immunostaining of SMC differentiation marker proteins (Desmin, Smoothelin, Myosin heavy chain (MHC)) were absent or only found in low numbers at the inner myometrium, while all of these marker proteins were clearly stained at the outer myometrium. In both types of adenomyotic foci, Desmin, Smoothelin, and MHC commonly showed a negative staining at the adjacent area to the glands. A significant staining of Non-muscle myosin IIB, TGF-β, and phosphorylated TGF-β type I receptors were found only at the SMCs of Subtype II adenomyosis. The Smad3/2 ratio of Subtype II adenomyosis was significantly higher than that of Subtype I.. The inner myometrium of normal uteri was composed of undifferentiated phenotypes of SMCs, while the outer myometrium was composed of terminally differentiated SMCs. Various fibrotic processes have been suggested in the development of uterine adenomyosis. Distinct expression patterns of fibrosis related proteins have been shown to be implicated with differences in the subtypes of adenomyosis.

Topics: Adenomyosis; Adult; Collagen Type I; Collagen Type III; Cytoskeleton; Female; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Middle Aged; Myometrium; Phenotype; Signal Transduction; Transforming Growth Factor beta; Young Adult