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Expression and localization of connective tissue growth factor (CTGF/Hcs24/CCN2) in osteoarthritic cartilage 总被引:1,自引:0,他引:1
Omoto S Nishida K Yamaai Y Shibahara M Nishida T Doi T Asahara H Nakanishi T Inoue H Takigawa M 《Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society》2004,12(10):771-778
OBJECTIVE: The investigation of the expression and localization of connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24/CCN family member 2 (CTGF/Hcs24/CCN2) in normal and osteoarthritic (OA) cartilage, and quantification of CTGF/Hcs24-positive cells. METHODS: Cartilage samples of patients (n=20) with late stage OA were obtained at total joint replacement surgery. Morphologically normal cartilage was harvested for comparison purposes from the femoral heads of 6 other patients with femoral neck fracture. Paraffin-embedded sections were stained by Safranin O. The severity of the OA lesions was divided into four stages (normal, early, moderate, and severe). The localization of protein and mRNA for CTGF/Hcs24 was investigated by immunohistochemistry and in situ hybridization, respectively. The population of CTGF/Hcs24-positive chondrocytes in OA cartilage and chondro-osteophyte was quantified by counting the number of the cells under light microscopy. RESULTS: Signals for CTGF/Hcs24 were detected in a small percentage of chondrocytes throughout the layers of normal cartilage. In early stage OA cartilage, the CTGF/Hcs24-positive chondrocytes were localized mainly in the superficial layer. In moderate to severe OA cartilage, intense staining for CTGF/Hcs24 was observed in proliferating chondrocytes forming cell clusters next to the cartilage surface. In chondro-osteophyte, strong signals were found in the chondrocytes of the proliferative and hypertrophic zones. CONCLUSION: CTGF/Hcs24 expression was detected in both normal and OA chondrocytes of human samples. The results of the current study suggested that expression of CTGF/Hcs24 was concomitant with development of OA lesions and chondrocyte differentiation in chondro-osteophyte. 相似文献
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Kubota S Eguchi T Shimo T Nishida T Hattori T Kondo S Nakanishi T Takigawa M 《BONE》2001,29(2):155-161
The synthesis, processing, and secretion of human connective tissue growth factor (CTGF/Hcs24) in a human chondrocytic cell line, HCS-2/8, were analyzed immunochemically. By metabolic pulse-labeling, chasing, and subsequent immunoprecipitation analyses, active synthesis of CTGF was observed not only in growing HCS-2/8 cells, but also in confluent cells. However, secretion and processing of CTGF were found to be regulated differentially, depending upon the growth status. During phases of growth, HCS-2/8 cells released CTGF molecules immediately without sequestering them within the cell layer. In contrast, after the cells reached confluence, the secretion slowed, resulting in an accumulation of CTGF in the cells or extracellular matrices (ECMs). Also, in confluent cell layers, a 10 kDa protein that was reactive to an anti-CTGF serum was observed. This CTGF-related small protein was not detected immediately after labeling, but gradually appeared within 6 h after chase, which suggests its entity as a processed subfragment of CTGF. Surprisingly, the 10 kDa protein was stable even 48 h after synthesis, and was not released by ECM digestion, suggesting an intracellular maintenance and function. Taken together, the behavior of CTGF in HCS-2/8 cells is remarkably different from that reported in fibroblasts, which may represent unique roles for CTGF in the growth and differentiation of chondrocytes. 相似文献
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S Kroening S Solomovitch M Sachs B Wullich M Goppelt-Struebe 《Nephrology, dialysis, transplantation》2009,24(3):755-762
BACKGROUND: Hepatocyte growth factor (HGF) is a pleiotropic protein with renoprotective functions, which have been attributed at least in part to its ability to counteract the profibrotic effects of transforming growth factor beta (TGF-beta). A major downstream mediator of TGF-beta is connective tissue growth factor (CTGF). However, the molecular mechanisms of CTGF regulation by HGF have not yet been investigated. METHODS: CTGF expression was analysed in human primary tubular epithelial cells (hPTECs) and the cell line HKC-8 by western blotting. Morphological alterations were analysed by immunocytochemistry. RESULTS: HGF induced a transient expression of CTGF, which was maximal after 6 h and returned to baseline after 24 h. Coincubation with TGF-beta increased CTGF protein at 6 h, whereas HGF significantly decreased CTGF induction by TGF-beta after 24 h. Furthermore, HGF induced cell scattering associated with reorganization of focal adhesions and formation of lamellipodia and filopodia. The early induction of CTGF was linked to the HGF-mediated alterations of cell morphology. The PP2 inhibitor of Src-family kinases, which regulate focal adhesion turnover, reduced HGF-mediated upregulation of CTGF. In addition, inhibition of the Rho-kinase, which modulates the actin cytoskeleton, impaired CTGF expression. Combination of both inhibitors further decreased CTGF expression. Comparable inhibitory effects were obtained, when CTGF was induced by the combination of HGF and TGF-beta. CONCLUSIONS: We provide evidence for a dual effect of HGF on CTGF regulation in human tubular epithelial cells: transient upregulation of CTGF in the absence of TGF-beta, which was related to alterations of cell morphology, and interference with TGF-beta-mediated CTGF induction after prolonged incubation. 相似文献
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结缔组织生长因子在椎间盘纤维化和退变中的表达和作用 总被引:1,自引:0,他引:1
目的研究疼痛椎间盘组织中结缔组织生长因子(connective tissue growth factor, CTGF)的表达及其在椎间盘纤维化和退变中的作用。方法收集腰椎后路融合过程中切除的43个疼痛的病理椎间盘,来自于28例行腰椎后路椎体间融合手术的严重椎间盘源性下腰痛患者;同时收集16个在MRIT2加权像信号强度明显减弱的无腰痛症状的退变椎间盘,取自于6例腰椎管狭窄症和8例多节段腰椎后路融合的患者(年龄44~75岁,平均53.5岁,男女比例为8:6)和8个正常对照椎间盘,来自于4具新鲜尸体标本(22~39岁,平均28岁)的L。和蛉.椎间盘。均行组织学检查并用免疫组化方法检测CTGF在不同椎间盘组织的表达。结果组织学检查发现,疼痛椎间盘组织显示不同程度的慢性血管化炎症反应。纤维环组织失去正常的胶原纤维板层结构,板层结构断裂、紊乱或相互交叉融合,正常的成纤维细胞被软骨细胞替代。髓核显示明显纤维化、血管浸润或形成炎性肉芽组织,软骨细胞被成纤维细胞所替代。免疫组化染色显示CTGF在疼痛椎间盘大量表达,无腰痛症状的退变椎间盘有少量表达,正常对照椎间盘没有表达。结论疼痛的退变椎间盘在组织学上明显不同于无腰痛症状的退变椎间盘。CTGF在疼痛椎间盘的大量表达可能与椎间盘纤维化和退变过程密切相关。 相似文献
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Fujisawa T Hattori T Ono M Uehara J Kubota S Kuboki T Takigawa M 《Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society》2008,16(7):787-795
OBJECTIVES: CCN family 2/connective tissue growth factor (CCN2/CTGF) is an atypical growth factor for growth plate chondrocytes. It plays an important role in their proliferation and differentiation in vitro, but does not stimulate hypertrophy or calcification of articular chondrocytes. We herein report for the first time that CCN2/CTGF promotes growth and differentiation of auricular chondrocytes and maintains their molecular phenotype in vitro and in vivo. METHODS: Auricular chondrocytes were isolated from rabbit auricular cartilage by trypsin-collagenase treatment, and treated with human recombinant CCN2/CTGF or infected with adenovirus harboring the ccn2/ctgf gene. Cell proliferation was measured by [(3)H] thymidine incorporation and MTS assay, and changes in gene expression of auricular chondrocyte markers were monitored by real-time polymerase chain reaction, Northern hybridization, and histological analysis. For in vivo studies, auricular chondrocytes were cultured as pellets and implanted subcutaneously after treatment of recombinant human CCN2/CTGF. Ectopically formed cartilage was subjected to histological analysis. Cell death was monitored by in situ TUNEL analysis. RESULTS: CCN2/CTGF stimulated proliferation, differentiation and synthesis of elastin and proteoglycans of rabbit primary auricular chondrocytes in a dose-dependent manner. CCN2/CTGF caused a 2.5-fold increase in the expression of elastin in comparison to the control, resulting in enhanced deposition of elastin fibers in a monolayer culture of auricular chondrocytes. Mineralization was not induced; in contrast, CCN2/CTGF stimulated expression of matrix gla protein which is known to impair mineralization. Furthermore, pretreatment of pellets of auricular chondrocytes with CCN2/CTGF and subcutaneous implantation significantly enhanced the growth of ectopic auricular cartilage pieces expressing phenotypic markers of auricular chondrocytes including type II and X collagen. Notably, chondrocyte apoptosis was impaired by CCN2/CTGF. CONCLUSIONS: These findings show that CCN2/CTGF may be a suitable agent for promoting differentiation and growth of auricular chondrocytes, while preventing mineralization and apoptosis, and suggests that CCN2/CTGF may be useful for the repair or reconstruction of elastic cartilage. 相似文献
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Pathogenic role of connective tissue growth factor (CTGF/CCN2) in osteolytic metastasis of breast cancer. 总被引:5,自引:0,他引:5
Tsuyoshi Shimo Satoshi Kubota Norie Yoshioka Soichiro Ibaragi Sachiko Isowa Takanori Eguchi Akira Sasaki Masaharu Takigawa 《Journal of bone and mineral research》2006,21(7):1045-1059
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S. Zhang D. Suzuki T. Umezono M. Toyoda H. Sakai 《Clinical and experimental nephrology》2001,5(1):33-39
Background. Connective tissue growth factor (CTGF) is a cysteine-rich member of a new family of growth regulators. Its upregulation is
an important factor in the pathogenesis of mesangial matrix accumulation and progressive glomerulosclerosis.
Methods. We evaluated the expression and localization of CTGF mRNA in renal tissues of 20 patients with IgA nephropathy (IgA-N) and
5 normal human kidneys (NHK), using high-resolution in situ hybridization with digoxigenin-labeled oligonucleotide. The expression
level of CTGF mRNA was quantitated by counting all nuclei, as well as nuclei surrounded by CTGF mRNA-positive cytoplasm in
at least ten randomly selected cross-sections of nonsclerotic glomeruli, and expressing the results as percentage of positive
cells.
Results. In both IgA-N and NHK, CTGF mRNA was mainly expressed in glomerular intrinsic cells, including mainly glomerular mesangial
and epithelial cells, and some endothelial cells and cells of Bowman's capsule. CTGF mRNA-positive cells were abundant in
tubulointerstitial fibrotic areas, especially in IgA-N with severe tissue damage. CTGF mRNA expression was also increased
in vascular cells in IgA-N. The percentage of cells positive for CTGF mRNA was significantly higher in IgA-N than in NHK.
Furthermore, the percentage of cells positive for CTGF mRNA was significantly greater in IgA-N with moderate mesangial proliferative
lesions than in IgA-N with mild mesangial proliferative lesions and/or sclerotic lesions.
Conclusions. Our study indicates that CTGF may play an important role in the development and progression of glomerulosclerosis and tubulointerstitial
fibrosis in IgA-N.
Received: July 17, 2000 / Accepted: October 21, 2000 相似文献
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目的:探讨结缔组织生长因子(CTGF)对纤维软骨细胞外基质分泌、VEGF表达及促进半月板无血管区的损伤修复中的作用。方法:将新西兰大白兔半月板白区,经胶原酶消化、离心分离后,提取半月板纤维软骨细胞,培养至第2代。用流式细胞仪鉴定该细胞表面CD31,CD44,CD45和CD105标志物,并用Ⅱ型胶原抗体做免疫细胞化学鉴定,以证明所培养、传代的细胞是纤维软骨细胞。分别将细胞培养在浓度100 ng/ml的CTGF培养基中3、14 d后,通过实时定量聚合酶链反应,检测Ⅰ型胶原、Ⅱ型胶原和VEGF基因的表达变化情况。造模,在兔半月板中央区,制作长3 mm的纵行撕裂。将45只大白兔随机分为3组,处理方式为:半月板单纯缝合术,缝合术加填充PBS-纤维蛋白胶,缝合术加填充1.5滋g CTGF-纤维蛋白胶。术后第1、4、10周用荧光免疫组织化学分析法显示Ⅰ型、Ⅱ型胶原和VEGF在损伤处的表达与分布情况,直观撕裂处的愈合情况。结果:体外实验第14天,定量RT-PCR结果显示,100 ng/ml CTGF组中的Ⅰ型、Ⅱ型胶原和VEGF mRNA表达比PBS对照组,明显增加。体内实验的荧光免疫组织化学结果显示,在术后第10周,CTGF治疗组中的Ⅰ型、Ⅱ型胶原和VEGF已完全填充撕裂损伤处。 PBS-蛋白胶组中,损伤处仍有明显裂隙。结论:CTGF可促进半月板无血管区重要的细胞外基质(Ⅰ型、Ⅱ型胶原)的合成,同时损伤处VEGF的表达活性明显增强,有利于促进无血管区半月板撕裂损伤的愈合。 相似文献
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Isbert C Ritz JP Roggan A Schuppan D Ajubi N Buhr HJ Hohenberger W Germer CT 《Lasers in surgery and medicine》2007,39(1):42-50
BACKGROUND AND OBJECTIVES: Proliferation and synthesis of hepatocellular tissue after tissue damage are promoted by specific growth factors such as hepatic tissue growth factor (HGF) and connective growth factor (CTGF). Laser-induced thermotherapy (LITT) for the treatment of liver metastases is deemed to be a parenchyma-saving procedure compared to hepatic resection. The aim of this study was to compare the impact of LITT and hepatic resection on intrahepatic residual tumor tissue and expression levels of mRNA HGF/CTGF within liver and tumor tissue. STUDY DESIGN/MATERIALS AND METHODS: Two independent adenocarcinomas (CC531) were implanted into 75 WAG rats, one in the right (untreated tumor) and one in the left liver lobe (treated tumor). The left lobe tumor was treated either by LITT or partial hepatectomy. The control tumor was submitted to in-situ hybridization of HGF and CTGF 24-96 hours and 14 days after intervention. RESULTS: Volumes of the untreated tumors prior to intervention were 38+/-8 mm(3) in group I (laser), 39 +/- 7 mm(3) in group II (resection), and 42 +/- 12 mm(3) in group III (control) and did not differ significantly (P > 0.05). Fourteen days after the intervention the mean tumor+/-SEM volume of untreated tumor in group I (laser) [223 +/- 36] was smaller than in group II (resection) [1233.28 +/- 181.52; P < 0.001], and in group III (control) [978.92 +/- 87.57; P < 0.003]. Forty-eight hours after the intervention intrahepatic mRNA expression level of HGF in group II (resection) was almost twofold higher than in group I (laser) [7.2 +/- 1.0 c/mf vs. 3.9 +/- 0.4 c/mf; P<0.01]. Fourteen days after the intervention intrahepatic mRNA expression level of CTGF in group I (laser) was higher than in group II (resection) [13.89 +/- 0.77 c/mf vs. 9.09 +/- 0.78 c/mf; P < 0.003]. CONCLUSIONS: LITT leads to a decrease of residual tumor growth in comparison to hepatic resection. Accelerated tumor growth after hepatic resection is associated with higher mRNA level of HGF and reduced tumor growth after LITT with higher mRNA level of CTGF. The increased CTGF-mediated regulation of ECM may cause reduced residual tumor growth after LITT. 相似文献
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Expression of parathyroid hormone-related peptide and insulin-like growth factor I during rat fracture healing. 总被引:4,自引:0,他引:4
Ken Okazaki Seiya Jingushi Takashi Ikenoue Ken Urabe Hiroaki Sakai Yukihide Iwamoto 《Journal of orthopaedic research》2003,21(3):511-520
Parathyroid hormone-related peptide (PTHrP) and insulin-like growth factor I (IGF-I) are both involved in the regulation of bone and cartilage metabolisms and their interaction has been reported in osteoblasts. To investigate the interaction of PTHrP and IGF-I during fracture healing, the expression of mRNA for PTHrP and IGF-I, and receptors for PTH/PTHrP and IGF were examined during rat femoral fracture healing using an in situ hybridization method and an immunohistochemistry method, respectively. During intramembranous ossification, PTHrP mRNA, IGF-I mRNA and IGF receptors were detected in preosteoblasts, differentiated osteoblasts and osteocytes in the newly formed trabecular bone. PTH/PTHrP receptors were markedly detected in osteoblasts and osteocytes, but only barely so in preosteoblasts. During cartilaginous callus formation, PTHrP mRNA was expressed by mesenchymal cells and proliferating chondrocytes. PTH/PTHrP receptors were detected in proliferating chondrocytes and early hypertrophic chondrocytes. IGF-I mRNA and IGF receptor were co-expressed by mesenchymal cells, proliferating chondrocytes, and early hypertrophic chondrocytes. At the endochondral ossification front, osteoblasts were positive for PTHrP and IGF-I mRNA as well as their receptors. These results suggest that IGF-I is involved in cell proliferation or differentiation in mesenchymal cells, periosteal cells, osteoblasts and chondrocytes in an autocrine and/or paracrine fashion. Furthermore, PTHrP may be involved in primary callus formation presumably co-operating with IGF-I in osteoblasts and osteocytes, and by regulating chondrocyte differentiation in endochondral ossification. 相似文献
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