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Transcriptional regulation of connective tissue growth factor by sphingosine 1-phosphate in rat cultured mesangial cells 总被引:3,自引:0,他引:3
Connective tissue growth factor (CTGF) is induced by transforming growth factor-beta (TGF-beta) via Smad activation in mesangial cells. We recently reported that sphingosine 1-phosphate (S1P) induces CTGF expression in rat cultured mesangial cells. However, the mechanism by which S1P induces CTGF expression is unknown. The present study revealed that S1P-induced CTGF expression is mediated via pertussis toxin-insensitive pathways, which are involved in the activation of small GTPases of the Rho family and protein kinase C. We also showed by luciferase reporter assays and chromatin immunoprecipitation that S1P induces CTGF expression via Smad activation as TGF-beta does. 相似文献
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Kawata K Eguchi T Kubota S Kawaki H Oka M Minagi S Takigawa M 《Biochemical and biophysical research communications》2006,345(2):552-559
Low density lipoprotein receptor (LDLR)-related protein 1 (LRP1/CD91) is one of the receptors of CCN2 that conducts endochondral ossification and cartilage repair. LRP1 is a well-known endocytic receptor, but its distribution among chondrocytes remains to be elucidated. We herein demonstrate for the first time that the distribution of LRP1 in chondrocytes except for hypertrophic chondrocytes in vivo and in vitro. Interestingly, the LRP1 levels were higher in mature chondrocytic HCS-2/8 and osteoblastic SaOS-2 than in other cells, whereas the other LDLR family members involved in ossification were detected at lower levels in HCS-2/8. It was interesting to note that in HCS-2/8, LRP1 was observed not only on the cell surface and in the cytoplasm, but also in the nucleus. Exogenously added CCN2 was incorporated into HCS-2/8, which was partially co-localized with LRP1, and targeted to the recycling endosomes and nucleus as well as the lysosomes. These findings suggest specific roles of LRP1 in cartilage biology. 相似文献
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Intratracheal gene transfer of tissue factor pathway inhibitor attenuates pulmonary fibrosis 总被引:1,自引:0,他引:1
Kijiyama N Ueno H Sugimoto I Sasaguri Y Yatera K Kido M Gabazza EC Suzuki K Hashimoto E Takeya H 《Biochemical and biophysical research communications》2006,339(4):1113-1119
Activation of the coagulation system and increased expression of tissue factor (TF) in pulmonary fibrosis associated with acute and chronic lung injury have been previously documented. In the present study, we evaluated the effect of TF inhibition with intratracheal gene transfer of tissue factor pathway inhibitor (TFPI), a potent and highly specific endogenous inhibitor of TF-dependent coagulation activation, in a rat model of bleomycin-induced lung fibrosis. Significant lung fibrotic changes as assessed by histologic findings and hydroxyproline content, and increased procoagulant activity and thrombin generation in bronchoalveolar lavage fluid were detected in rats after intratracheal injection of bleomycin. Intratracheal administration of an adenovirus vector expressing TFPI significantly decreased bleomycin-induced procoagulant and thrombin generation resulting in a strong inhibition of pulmonary fibrosis. TFPI-overexpression in the lung was associated with a significant reduction in gene expression of the connective tissue growth factor, a potent profibrotic growth factor. This is the first report showing that direct inhibition of TF-mediated coagulation activation abrogates bleomycin-induced pulmonary fibrosis. 相似文献
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Borkham-Kamphorst E van Roeyen CR Van de Leur E Floege J Weiskirchen R 《Journal of cell communication and signaling》2012,6(1):11-25
Nephroblastoma overexpressed gene encodes a matricellular protein (CCN3/NOV) of the CCN family, comprising CCN1 (CYR61), CCN2
(CTGF), CCN4 (WISP-1), CCN5 (WISP-2), and CCN6 (WISP-3). CCN proteins are involved in the regulation of mitosis, adhesion,
apoptosis, extracellular matrix production, growth arrest and migration in multiple cell types. Compared to CCN2/CTGF, known
as a profibrotic protein, the biological role of CCN3/NOV in liver fibrosis remains obscure. In this study we showed ccn3/nov mRNA to increase dramatically following hepatic stellate cell activation, reaching peak levels in fully transdifferentiated
myofibroblasts. In models of experimental hepatic fibrosis, CCN3/NOV increased significantly at the mRNA and protein levels.
CCN3/NOV was found mainly in non-parenchymal cells along the areas of tissue damage and repair. In the bile-duct ligation
model, CCN3/NOV was localized mainly along portal tracts, while the repeated application of carbon tetrachloride resulted
in CCN3/NOV expression mainly in the centrilobular areas. In contrast to CCN2/CTGF, the profibrotic cytokines platelet-derived
growth factor-B and -D as well as transforming growth factor-β suppressed CCN3/NOV expression. In vitro, CCN3/NOV siRNA attenuated
migration in the cirrhotic fat storing cell line CFSC well in line with in vivo findings that various types of cells expressing
CCN3/NOV migrate into the area of tissue damage and regeneration. The suppression of CCN3/NOV enhanced expression of profibrotic
marker proteins, such as α-smooth muscle actin, collagen type I, fibronectin, CCN2/CTGF and TIMP-1 in primary rat hepatic
stellate cells and in CFSC. We further found that adenoviral overexpression of CCN2/CTGF suppressed CCN3/NOV expression, while
the overexpression of CCN3/NOV as well as the suppression of CCN3/NOV by targeting siRNAs both resulted in enhanced CCN2/CTGF
expression. These results indicate the complexity of CCN actions that are far beyond the classic Yin/Yang interplay. 相似文献
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Tadashi Honjo Satoshi Kubota Hiroshi Kamioka Yasuyo Sugawara Yoshihito Ishihara Takashi Yamashiro Masaharu Takigawa Teruko Takano-Yamamoto 《Journal of cell communication and signaling》2012,6(4):225-232
Fluid flow stress (FSS) is a major mechanical stress that induces bone remodeling upon orthodontic tooth movement, whereas CCN family protein 2 (CCN2) is a potent regenerator of bone defects. In this study, we initially evaluated the effect of laminar FSS on Ccn2 expression and investigated its mechanism in osteoblastic MC3T3-E1 cells. The Ccn2 expression was drastically induced by uniform FSS in an intensity dependent manner. Of note, the observed effect was inhibited by a Rho kinase inhibitor Y27632. Moreover, the inhibition of actin polymerization blocked the FSS-induced activation of Ccn2, whereas inducing F-actin formation using cytochalasin D and jasplakinolide enhanced Ccn2 expression in the same cells. Finally, F-actin formation was found to induce osteoblastic differentiation. In addition, activation of cyclic AMP-dependent kinase, which inhibits Rho signaling, abolished the effect of FSS. Collectively, these findings indicate the critical role of actin polymerization and Rho signaling in CCN2 induction and bone remodeling provoked by FSS. 相似文献
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Makiko Fujii Hayao Nakanishi Takeshi Toyoda Ichidai Tanaka Yutaka Kondo Hirotaka Osada Yoshitaka Sekido 《Cell cycle (Georgetown, Tex.)》2012,11(18):3373-3379
Malignant mesothelioma (MM) is a neoplasm that arises from serosal surfaces of the pleural, peritoneal and pericardial cavities with worldwide incidence, much of which is caused by asbestos exposure. Patients suffer from pain and dyspnea due to direct invasion of the chest wall, lungs and vertebral or intercostal nerves by masses of thick fibrotic tumors. Although there has been recent progress in the clinical treatment, current therapeutic approaches do not provide satisfactory results. Therefore, development of a molecularly targeted therapy for MM is urgently required. Our recent studies suggest that normal mesothelial and MM cell growth is promoted by TGFβ, and that TGFβ signaling together with intrinsic disturbances in neurofibromatosis type 2 (NF2) and Hippo signaling cascades in MM cells converges upon further expression of connective tissue growth factor (CTGF). The formation of a YAP-TEAD4–Smad3-p300 complex on the specific CTGF promoter site with an adjacent TEAD and Smad binding motif is a critical and synergistic event caused by the dysregulation of these two distinct cascades. Furthermore, we demonstrated the functional importance of CTGF through the mouse studies and human histological analyses, which may elucidate the clinical features of MM with severe fibrosis in the thoracic cavity. 相似文献
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This study is carried out to investigate the role of microRNA-26a (miR-26a) in cartilage injury and chondrocyte proliferation and apoptosis in rats with rheumatoid arthritis (RA) by regulating expression of CTGF. A rat model of RA induced by type II collagen was established. The rats were assigned into normal, RA, RA + mimics negative control (NC), and RA + miR-26a mimics groups, and the cells were classified into blank, mimics NC, and miR-26a mimics groups. The degree of secondary joint swelling and arthritis index, expression of miR-26a, pathological changes, proliferation and apoptosis of chondrocytes, and expression of CTGF, interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α, Bax, and Bcl-2 were also determined through a series of experiments. The targeting relationship between miR-26a and CTGF was verified. Initially, downregulated miR-26a was found in cartilage tissues and inflammatory articular chondrocytes of RA rats. In addition, CTGF was determined as a direct target gene of miR-26a, and upregulation of miR-26a inhibited CTGF expression in cartilage tissues of RA rats. Furthermore, upregulation of miR-26a reduced swelling and inflammation of joints, inhibited cartilage damage, apoptosis of chondrocytes, inflammatory injury, promotes proliferation, and inhibited apoptosis of inflammatory articular chondrocytes, which may be correlated with the targeting inhibition of CTGF expression. Collectively, the results demonstrate that upregulating the expression of miR-26a could attenuate cartilage injury, stimulate the proliferation, and inhibit apoptosis of chondrocytes in RA rats. 相似文献