The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
Whether environmental toxicants impact an individual woman's risk for developing endometriosis remains uncertain. Although the growth of endometrial glands and stroma at extra-uterine sites is associated with retrograde menstruation, our studies suggest that reduced responsiveness to progesterone may increase the invasive capacity of endometrial tissue in women with endometriosis. Interestingly, our recent studies using isolated human endometrial cells in short-term culture suggest that experimental exposure to the environmental contaminant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) can alter the expression of progesterone receptor isotypes. Compared to adult exposure, toxicant exposure during development can exert a significantly greater biological impact, potentially affecting the incidence of endometriosis in adults. To address this possibility, we exposed mice to TCDD at critical developmental time points and subsequently examined uterine progesterone receptor expression and steroid responsive transforming growth factor-beta2 expression in adult animals. We find that the uterine phenotype of toxicant-exposed mice is markedly similarly to the endometrial phenotype of women with endometriosis.
We have previously shown that expression of a dominant-negative type II transforming growth factor-beta receptor (DNIIR) in mammary epithelium under control of the MMTV promoter/enhancer causes alveolar hyperplasia and differentiation in virgin mice. Here we show that MMTV-DNIIR female mice have accelerated mammary gland differentiation during early pregnancy with impaired development during late pregnancy and lactation followed by delayed postlactational involution. Mammary tumors, mostly carcinoma in situ, developed spontaneously in the MMTV-DNIIR mice with a long median latency (27.5 months). Crossbreeding to MMTV-transforming growth factor (TGF)-alpha mice to obtain mice expressing both transgenes resulted in mammary tumor formation with a much shorter latency more similar to those expressing only the MMTV-TGF-alpha transgene (<10 months median latency). The major difference in mammary tumors arising in MMTV-TGF-alpha compared to bigenic MMTV-DNIIR/MMTV-TGF-alpha was the marked suppression of tumor invasion by DNIIR transgene expression. Invading carcinoma cells in both MMTV-DNIIR and bigenic animals showed loss of DNIIR transgene expression as determined by in situ hybridization. The data indicate that signaling from endogenous TGF-betas not only plays an important role in normal mammary gland physiology but also can also suppress the early stage of tumor formation and contribute to tumor invasion once carcinomas have developed.
Proper septation and valvulogenesis during cardiogenesis depend on interactions between the myocardium and the endocardium. By combining use of a hypomorphic Bone morphogenetic protein 4 (Bmp4) allele with conditional gene inactivation, we here identify Bmp4 as a signal from the myocardium directly mediating atrioventricular septation. Defects in this process cause one of the most common human congenital heart abnormalities, atrioventricular canal defect (AVCD). The spectrum of defects obtained through altering Bmp4 expression in the myocardium recapitulates the range of AVCDs diagnosed in patients, thus providing a useful genetic model with AVCD as the primary defect.
Ligament injuries result in significant disability in over 100,000 patients each year. Despite current methods of treatment, 13% of patients with medial collateral ligament (MCL) injury develop early signs of arthritis, suggesting an incomplete return of knee stability. The principal hypothesis of this work was that the addition of TGF-beta 2 to the healing MCL would accelerate the development of scar strength and stiffness. Forty-four rabbits were divided evenly into four groups, with each group receiving either 0.1, 1 or 5 microg of TGF-beta 2 and the fourth group receiving 1 microg TGF-beta 2 and 1 microg of PDGF. Each rabbit underwent bilateral transection of the MCL, with one side having treatment with one of four doses of growth factor and the other side left untreated. All animals were sacrificed at 6 weeks and the structural properties of maximum load at failure, stiffness, and energy absorbed at failure measured. All treatment groups demonstrated an increase in scar mass, but no group had a significant increase in scar load at failure at 6 weeks. The addition of 0.1 microg TGF-beta 2 led to a significant increase in scar stiffness. The addition of PDGF had no significant effect on any of the parameters studied. This study suggests the mechanical stiffness, but not the load at failure, of ligament scar can be significantly altered by the administration of TGF-beta 2.
We investigated biomechanical and collagen expression in a healing bilateral rabbit medial collateral ligament (MCL) model to human recombinant transforming growth factor beta (rhTGF-beta2) at three and six weeks. Each rabbit had rhTGF-beta2 in a bioabsorbable pellet administered in one side, with the contralateral side serving as control (no rhTGF-beta2). All MCL healed with rhTGF-beta2 producing a profoundly increased scar mass at three weeks which decreased in size toward control at six weeks. In-situ hybridization demonstrated collagen expression (type I and III) no different than control at three weeks, but by six weeks elevated expression of type I was seen. Biomechanical analysis at three weeks showed no effect of rhTGF-beta2 on structural properties. However, at six weeks rhTGF-beta2 significantly inhibited both the maximum load (p < 0.05) and energy absorbed (p < 0.05) with no change in stiffness. Despite increased type I collagen expression and profound increase in early scar mass, rhTGF-beta2 did not improve the structural properties. Whether the dose or mode of delivery is responsible for decline in structural properties cannot be determined in this design. We hypothesize investigations of healing ligaments to cytokines should have biologic and biomechanical properties correlated in the same study at a minimum of two time points.
Many studies have suggested that transforming growth factor beta (TGF-beta) and bone morphogenetic protein 4 (Bmp4) regulate early development of the lung. In this study, administration of growth factors directly into the lumen of lungs grown in organ culture was used to limit their activity to the epithelium and test the hypothesis that signaling to the epithelium is sufficient to mediate the known effects of TGF-beta and BMP-4 on early lung development. Addition of TGF-beta1, beta2, or beta3 to the medium surrounding lungs grown in organ culture resulted in decreased branching, reduced cell proliferation, accumulation of alpha-smooth muscle actin protein (alpha-SMA) in the mesenchyme, and decreased expression of a marker for respiratory epithelium, surfactant protein-C (Sp-C). When TGF-beta1 was restricted to the epithelium, accumulation of alpha-SMA and inhibition of Sp-C expression were not observed but branching and proliferation were inhibited. In contrast, branching was not inhibited in lungs where TGF-beta2 or TGF-beta3 were restricted to the epithelium suggesting differences in the mechanism of signaling by TGF-beta1, TGF-beta2 or TGF -beta3 in lung. Addition of Bmp4 to the medium surrounding lungs grown in organ culture stimulated cell proliferation and branching morphogenesis; however, direct injection of Bmp4 into the lung lumen had no effect on proliferation or branching. Based on these data and data from mesenchyme-free cultures, we propose that the mesenchyme influences growth factor signaling in the lung.