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PubMed1997

Connective tissue growth factor. Friend or foe?

Connective tissue growth factor (CTGF) is a novel cysteine-rich, secreted peptide, which is implicated in human atherosclerosis and fibrotic disorders such as systemic scleroderma. CTGF is a member of the peptide family that includes serum-induced immediate early gene products, a v-src-induced peptide, and a putative proto-oncogene. The CTGF gene family is a modular protein and is conserved throughout evolution. CTGF mRNA has been found in the human, mouse, chicken, frog, and fly. The functions of the CTGF gene family include embryogenesis, wound healing, and regulation of extracellular matrix production. Human CTGF is undetectable in normal blood vessels but overexpressed in atherosclerotic lesions, suggesting an important role in atherogenesis.

Connective Tissue Growth Factor↗

PubMed2003

Role of connective tissue growth factor in mediating hypertrophy of human proximal tubular cells induced by angiotensin II.

BACKGROUND/AIMS: Cellular hypertrophy is an early important pathological feature of renal diseases such as diabetic nephropathy and remnant kidney. Recent studies have demonstrated that angiotensin II (Ang II) might be a major contributor in regulating cell hypertrophy. However, the exact mechanism is still unclear. The aim of our present work was to investigate the possible role of a newly clarified fibrogenic factor, connective tissue growth factor (CTGF), in mediating the effect of Ang II-induced tubular cell hypertrophy. METHODS: The cell line HK2 was grown in Dulbecco's modified Eagle's medium containing 10% heat-inactivated fetal calf serum. After the cells were rested in serum-free medium for 24 h, the dose and time response of CTGF mRNA expression to Ang II stimulation was observed by RT-PCR, and protein synthesis was observed by Western blotting. The effect of anti-CTGF on Ang II (10(-7)M)-induced [(3)H]-leucine incorporation, total protein content (Coomassie brilliant blue G250 method) and change in cellular size [determined by a scanning electronic microscope (SEM)] was also observed. The influence of anti-CTGF antibody on the cell cycle was analyzed by using a fluorescence-activated cell sorter flow cytometer. RESULTS: The results showed that Ang II induced expression of CTGF mRNA in a time- and dose-dependent manner (p < 0.05 and 0.01, respectively). Stimulation of cells with Ang II (10(-7)M) for 48 h resulted in a 92% increase in [(3)H]-leucine incorporation (5,584 cpm/10(5) cells at 0 h vs. 10,741 cpm/10(5) cells at 48 h; p = 0.01), which was significantly abolished by treatment with anti-CTGF antibody. Ang II (10(-7)M) significantly increased the total protein content in HK2 cells (control: 0.169 +/- 0.011 mg/10(5) cells vs. Ang II: 0.202 +/- 0.010 mg/10(5) cells; p = 0.03), which was markedly inhibited by cotreatment with anti-CTGF antibody. The average cellular diameter determined by SEM showed that the increase in cell size induced by Ang II could be significantly inhibited by anti-CTGF antibody (control: 11.92 +/- 1.62 microm, Ang II group: 20.63 +/- 3.83 microm, Ang II + anti-CTGF group: 16.43 +/- 3.23 microm; p < 0.01, respectively). Furthermore, the flow cytometer study showed that Ang II arrested the cell cycle at G0-G1 phase, which was significantly reversed by treatment with anti-CTGF antibody (G0-G1 percentage: in Ang II group: 76 +/- 1.8%, in Ang II + anti-CTGF group: 71 +/- 1.78%; p = 0.04). CONCLUSION: Our data are the first to clearly demonstrate that CTGF might be an important mediator of Ang II-induced renal hypertrophy, which suggests that inhibiting the production of CTGF might be the new strategy in early prevention of renal fibrosis.

Angiotensin II↗

PubMed2002

Expression of connective tissue growth factor in intra-abdominal adhesions.

PURPOSE: Connective tissue growth factor stimulates fibroblast proliferation and extracellular matrix deposition in many fibrotic disorders. The aim of our study was to determine the expression pattern of connective tissue growth factor in postoperative intra-abdominal adhesions. METHODS: Adhesions were created in 46 Sprague-Dawley rats by complete dissection and resuturing of a peritoneal patch 2 cm in diameter, lateral from the midline incision. Animals were killed at postoperative Days 3, 6, 9, 12, 15, 18, and 21 and the adhesions scored on a scale of 0 to 5. Tissue samples from adhesion areas and from uninvolved peritoneum were evaluated by Northern and Western blotting for temporal connective tissue growth factor mRNA and protein expression, respectively. Immunohistochemical analysis was performed for connective tissue growth factor localization. RESULTS: Adhesions formed in all animals after surgery and were confined to the peritoneal patches. Adhesion formation increased across time, with significant correlation between adhesion scores and postoperative days (r = 0.329, P = 0.026). Connective tissue growth factor mRNA concentrations were significantly elevated in adhesion tissue throughout the three-week period when compared with normal peritoneum (P = 0.012); peak levels occurred between Days 6 and 15. Western blots demonstrated connective tissue growth factor protein expression in adhesions from Days 6 to 21, in contrast to negligible bands in normal peritoneum. Fibroblasts within the adhesive tissue, but not in uninjured peritoneum, stained positive for connective tissue growth factor by immunohistochemistry. CONCLUSIONS: We have demonstrated a specific temporal and spatial expression pattern for connective tissue growth factor in intra-abdominal adhesions during a three-week postoperative time course. According to what is known about the functional role of connective tissue growth factor in fibrogenesis, our findings warrant further investigations addressing a causal relationship between this growth factor and fibrous adhesion formation.

Animals↗

PubMed2000

The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts.

The angiogenic inducers cysteine-rich angiogenic protein 61 (Cyr61) and connective tissue growth factor (CTGF) are structurally related, extracellular matrix-associated heparin-binding proteins. Both can stimulate chemotaxis and promote proliferation in endothelial cells and fibroblasts in culture and induce neovascularization in vivo. Encoded by inducible immediate early genes, Cyr61 and CTGF are synthesized upon growth factor stimulation in cultured fibroblasts and during cutaneous wound healing in dermal fibroblasts. Recently, we have shown that adhesion of primary human fibroblasts to immobilized Cyr61 is mediated through integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans (HSPGs) (Chen, N., Chen, C.-C., and Lau, L.F. (2000) J. Biol. Chem. 275, 24953-24961), providing the first demonstration of an absolute requirement for HSPGs in integrin-mediated cell attachment. We show in this study that CTGF also mediates fibroblast adhesion through the same mechanism and demonstrate that fibroblasts adhesion to immobilized Cyr61 or CTGF induces distinct adhesive signaling responses consistent with their biological activities. Compared with fibroblast adhesion to fibronectin, laminin, or type I collagen, cell adhesion to Cyr61 or CTGF induces 1) more extensive and prolonged formation of filopodia and lamellipodia, concomitant with formation of integrin alpha(6)beta(1)-containing focal complexes localized at leading edges of pseudopods; 2) activation of intracellular signaling molecules including focal adhesion kinase, paxillin, and Rac with similar rapid kinetics; 3) sustained activation of p42/p44 MAPKs lasting for at least 9 h; and 4) prolonged gene expression changes including up-regulation of MMP-1 (collagenase-1) and MMP-3 (stromelysin-1) mRNAs and proteins sustained for at least 24 h. Together, these results establish Cyr61 and CTGF as bona fide adhesive substrates with specific signaling capabilities, provide a molecular basis for their activities in fibroblasts through integrin alpha(6)beta(1) and HSPG-mediated signaling during attachment and indicate that these proteins may function in matrix remodeling through the activation of metalloproteinases during angiogenesis and wound healing.

Cell Adhesion↗

PubMedDate not supplied

Connective tissue growth factor is directly related to liver fibrosis.

BACKGROUND/AIMS: Connective tissue growth factor is a mitogenic, chemotactic, and cell matrix-inducing factor for fibroblasts, and is exclusively and directly induced by transforming growth factor-beta 1. In skin fibrosis, connective tissue growth factor is thought to be a downstream effector of transforming growth factor-beta 1 that is directly involved in the proliferation of connective tissue cells and the accumulation of matrix. Our aim is to confirm the involvement of connective tissue growth factor in liver fibrosis. METHODOLOGY: Specimens obtained from autopsy of 12 patients with normal liver (n = 3), hepatocellular carcinoma (n = 3), liver cirrhosis secondary to alcoholic abuse (n = 3), or viral hepatitis (n = 3), were used for digoxigenin labeled in situ hybridization. RESULTS: Abundant connective tissue growth factor messages were detected in the fibrotic area between cirrhotic nodules. Hepatocytes did not show any signals even when they became carcinomas. Normal livers showed few or no signals. CONCLUSIONS: These results confirmed the direct relationship between connective tissue growth factor gene expression and liver fibrotic change.

Carcinoma, Hepatocellular↗

PubMed2002

Connective tissue growth factor: expression in human skin in vivo and inhibition by ultraviolet irradiation.

Connective tissue growth factor, which is induced by transforming growth factor beta, has been reported to mediate the stimulatory actions of transforming growth factor beta on type I procollagen synthesis. Connective tissue growth factor is expressed in fibrotic disease such as scleroderma, where it is believed to promote abnormal deposition of collagen. Connective tissue growth factor expression has not been described in normal human skin or cultured skin cells, however. We report here that connective tissue growth factor mRNA is constitutively expressed in normal human skin. In situ hybridization demonstrated that connective tissue growth factor mRNA was expressed in keratinocytes throughout the epidermis and in dermal cells. Quantitative real-time reverse transcription polymerase chain reaction revealed that the level of connective tissue growth factor mRNA in the epidermis and dermis of normal human skin was comparable to the level of housekeeping gene 36B4. Ultraviolet irradiation (2 minimal erythema dose, UVB/A2 source) reduced connective tissue growth factor mRNA expression throughout the epidermis and dermis in normal human skin in vivo. Connective tissue growth factor mRNA was reduced (30%) within 4 h post ultraviolet irradiation, and remained reduced (50%) 8-24 h post ultraviolet. Connective tissue growth factor mRNA and protein were also constitutively highly expressed in normal cultured human skin keratinocytes and fibroblasts. Ultraviolet irradiation of cultured normal human skin fibroblasts resulted in a time-dependent inhibition of connective tissue growth factor mRNA expression. At 24 h post ultraviolet, connective tissue growth factor mRNA expression was reduced 80%. Transforming growth factor beta1 rapidly induced connective tissue growth factor mRNA levels (5-fold within 4 h) in skin fibroblasts, but not keratinocytes, and this induction was attenuated 80% by ultraviolet irradiation. Electrophoretic mobility shift assays demonstrated that ultraviolet irradiation reduced protein binding to the transforming growth factor beta/Smad responsiveness elements in the connective tissue growth factor gene promoter, in human skin in vivo and human skin fibroblasts. Constitutive expression of connective tissue growth factor in normal human skin suggests that it is a physiologic regulator of procollagen synthesis. Ultraviolet reduction of connective tissue growth factor expression may contribute to reduced procollagen synthesis observed in ultraviolet-irradiated normal human skin and human skin fibroblasts.

Adult↗

PubMed2005

Connective tissue growth factor induces extracellular matrix in asthmatic airway smooth muscle.

Transforming growth factor (TGF)-beta and connective tissue growth factor may be implicated in extracellular matrix protein deposition in asthma. We have recently reported that TGF-beta increased connective tissue growth factor expression in airway smooth muscle cells isolated from patients with asthma. In this study, we examined fibronectin and collagen production and signal transduction pathways after stimulation with TGF-beta and connective tissue growth factor. In both asthmatic and nonasthmatic airway smooth muscle cells, TGF-beta and connective tissue growth factor led to the production of fibronectin and collagen I. Fibronectin and collagen expression was extracellular regulated kinase-dependent in both cell types but phosphoinositide-3 kinase-dependent only in asthmatic airway smooth muscle cells. p38 was implicated in fibronectin but not collagen expression in both cell types. TGF-beta induction of fibronectin and collagen was in part mediated by an autocrine action of connective tissue growth factor. Phosphorylation of SMAD-2 may represent an additional pathway because this was increased in asthmatic cells. Our results suggest that these two cytokines may be important in the deposition of extracellular matrix proteins and that the signal transduction pathways may be different in asthmatic and nonasthmatic cells.

Adolescent↗

PubMed2001

Proliferating bile duct epithelial cells are a major source of connective tissue growth factor in rat biliary fibrosis.

Connective tissue growth factor (CTGF) is a downstream mediator of transforming growth factor-beta1 (TGF-beta1) and thus a potential target for antifibrotic treatment strategies. CTGF is up-regulated in disorders such as atherosclerosis, scleroderma, and fibrosis of kidneys and lungs. We investigated the temporospatial expression patterns of CTGF and TGF-beta1 mRNA in rat livers with acute fibrogenesis (after a single dose of CCl(4)) and with advanced fibrosis (6 weeks after complete bile duct occlusion). Multiprobe ribonuclease protection assay revealed increasing TGF-beta1 and CTGF mRNA levels 6 hours after injection of CCl(4), with peak levels after 72 hours. In biliary fibrosis TGF-beta1 and CTGF mRNA levels increased fourfold and sevenfold, respectively (P: < 0.001). In situ hybridization combined with cell-specific markers revealed CTGF transcripts in desmin-positive cells after a single dose of carbon tetrachloride, whereas no transcripts were found in normal livers. In biliary fibrosis, however, proliferating bile duct epithelial cells were the predominant source of CTGF mRNA. We conclude that in rat liver fibrogenesis CTGF is up-regulated in close association with TGF-beta1 and that, contrary to a previous report, not solely hepatic stellate cells but activated bile duct epithelial cells are the main source of this profibrogenic factor.

Acute Disease↗

PubMed2006

Hypoxia induces expression of connective tissue growth factor in scleroderma skin fibroblasts.

Connective tissue growth factor (CTGF) plays a role in the fibrotic process of systemic sclerosis (SSc). Because hypoxia is associated with fibrosis in several profibrogenic conditions, we investigated whether CTGF expression in SSc fibroblasts is regulated by hypoxia. Dermal fibroblasts from patients with SSc and healthy controls were cultured in the presence of hypoxia or cobalt chloride (CoCl(2)), a chemical inducer of hypoxia-inducible factor (HIF)-1alpha. Expression of CTGF was evaluated by Northern and Western blot analyses. Dermal fibroblasts exposed to hypoxia (1% O(2)) or CoCl(2) (1-100 microM) enhanced expression of CTGF mRNA. Skin fibroblasts transfected with HIF-1alpha showed the increased levels of CTGF protein and mRNA, as well as nuclear staining of HIF-1alpha, which was enhanced further by treatment of CoCl(2). Simultaneous treatment of CoCl(2) and transforming growth factor (TGF)-beta additively increased CTGF mRNA in dermal fibroblasts. Interferon-gamma inhibited the TGF-beta-induced CTGF mRNA expression dose-dependently in dermal fibroblasts, but they failed to hamper the CoCl(2)-induced CTGF mRNA expression. In addition, CoCl(2) treatment increased nuclear factor (NF)-kappaB binding activity for CTGF mRNA, while decreasing IkappaBalpha expression in dermal fibroblasts. Our data suggest that hypoxia, caused possibly by microvascular alterations, up-regulates CTGF expression through the activation of HIF-1alpha in dermal fibroblasts of SSc patients, and thereby contributes to the progression of skin fibrosis.

Cell Hypoxia↗

PubMed2005

Gene expression of connective tissue growth factor in adult mouse.

The connective tissue growth factor (CTGF) is a well-known fibroblast mitogen and angiogenic factor that plays an important role in bone formation during embryogenesis. In the adult, CTGF is involved in wound healing as well as fibrotic and vascular disease. However, little is known about its physiological functions under non-pathological conditions in the adult organism. Here, we describe the cellular site of the CTGF mRNA expression in adult male and female mice as revealed by in situ hybridization histochemistry. Strong and persistent CTGF gene expression was particularly prominent in the mesenchyme of the cardiovascular system (aorta, auricular tissue, renal glomeruli), the mesenchyme surrounding the ovarian follicles or the testicular tubes in the gonadal tissue, and the subcapsular mesenchyme bordering densely innervated parts of whisker hair vibrissae. CTGF hybridization signals were not observed in the mesenchyme of many other organs including gut, muscle, liver or most parts of the lymphatic tissue. Strong expression was also present in the primary (early) ovarian follicles, the epithelium of the deep uterine glands and on myenteric ganglia neurons. These data suggest a selective and continuous mesenchymal function in the gonads and those tissues attracting very strong vascular supply or peripheral innervation. CTGF may also be involved in the cyclical proliferation of the uterine gland epithelium and in the early stages of follicular maturation, as well as in the neuropeptide regulation in the gut, cardiovascular and renal systems.

Animals↗

PubMed2002

Effects and regulation of connective tissue growth factor on hepatic stellate cells.

Connective tissue growth factor (CTGF) is a 38-kd protein involved in several human fibrotic disorders including atherosclerosis and skin and renal fibrosis. Although it has been shown that human and experimental liver fibrosis is associated with CTGF expression through up-regulation of CTGF mRNA by hepatic stellate cells (HSC), the role of CTGF in the liver has not yet been determined. The aim of the present study was to assess the effects of CTGF on rat primary HSC and its regulation in a well-established model of in vitro liver fibrogenesis. Incubation of primary HSC with recombinant CTGF induced a significant migratory (2.3-fold, 50 ng/ml CTGF) and proliferative effect (1.8-fold, 100 ng/ml CTGF). Type I collagen mRNA expression, as assessed by a real-time RT-PCR procedure, was also increased when cells were incubated in the presence of CTGF (2-fold, 50 ng/ml). Transforming growth factor-beta1 (TGF-beta1) strongly stimulated CTGF mRNA expression, a direct mechanism observed in the absence of any intermediate protein synthesis. Furthermore, spontaneous activation of HSC plated on plastic and stimulation by vascular endothelial growth factor, lipid peroxidation products (HNE, MDA), acetaldehyde, and platelet-derived growth factor (PDGF)-BB significantly up-regulated CTGF mRNA expression in HSC. PDGF-induced CTGF stimulation might be related in part to TGF-beta1 secretion because CTGF mRNA up-regulation observed after PDGF-BB stimulation was abrogated in the presence of neutralizing TGF-beta1 antibody. In conclusion, this study extends the role of CTGF in HSC activation and suggests that CTGF up-regulation might be a central pathway during HSC activation.

Animals↗

PubMed2004

In situ expression of connective tissue growth factor in human crescentic glomerulonephritis.

Connective tissue growth factor (CTGF) has recently been recognized as an important profibrotic factor and is up-regulated in various renal diseases with fibrosis. The present study describes the sequential localization of CTGF mRNA and its association with transforming growth factor (TGF)-beta1 in human crescentic glomerulonephritis (CRGN). Furthermore, we examined the phenotype of CTGF-expressing cells using serial section analysis. Kidney biopsy specimens from 18 CRGN patients were examined using in situ hybridization and immunohistochemistry. CTGF mRNA was expressed in the podocytes and parietal epithelial cells (PECs) in unaffected glomeruli. In addition, it was strongly expressed in the cellular and fibrocellular crescents, particularly in pseudotubule structures. Serial sections revealed that the majority of CTGF mRNA-positive cells in the crescents co-expressed the epithelial marker cytokeratin, but not a marker for macrophages. Moreover, TGF-beta1, its receptor TGF-beta receptor-I, and extracellular matrix molecules (collagen type I and fibronectin) were co-localized with CTGF mRNA-positive crescents. Our results suggest that CTGF is involved in extracellular matrix production in PECs and that it is one of the mediators promoting the scarring process in glomerular crescents.

Activin Receptors, Type I↗

PubMed2006

[p42/44 MAPK mediates synthesis of fractalkine by mesangial cells stimulated by connective tissue growth factor].

AIM: To examine whether connective tissue growth factor(CTGF) induces the production of fractalkine(FLK) by glomerular mesangial cells of rats, and explore the mechanism of signal pathway of CTGF actions. METHODS: The mRNA expression of FLK was analyzed by RT-PCR in cultured mesangial cells stimulated by CTGF. The protein of FLK in the supernatants of cells was determined by ELISA. The chemotactic effect of the supernatants on monocytes was assessed by the in vitro chemotaxis assay. The phosphorylation of p42/44 MAPK was assessed by Western blot. RESULTS: Treatment of the cells with CTGF enhanced the mRNA expression of FLK and concentration of FLK in the supernatants. Pretreatment of the supernatants of CTGF-treated cells with anti-FLK antibodies partially inhibited the chemotactic effect of the supernatants on monocytes. CTGF increased the p42/44MAPK phosphorylation. Pretreatment of the cells with PD98059 or UO126, inhibitors of phosphorylated p42/44 MAKP, decreased the CTGF-induced expression of phosphorylated p42/44 MAPK and concentration of FLK in supernatants. CONCLUSION: CTGF-induced secretion of FLK by mesangial cells was associated with the phosphorylation of p24/p44 MAPK.

Animals↗

PubMed2000

Expression of connective tissue growth factor in cartilaginous tumors.

BACKGROUND: Connective tissue growth factor (CTGF) predominantly is expressed in hypertrophic chondrocytes and its specific receptors are demonstrated on chondrocytic cells. Therefore, CTGF may be involved in the proliferation and/or differentiation of cartilage cells. In the current study, CTGF expression was examined both in chondrosarcoma and enchondroma to clarify the relation between the expression of CTGF and the grade of malignancy. METHODS: The expression of CTGF and proliferating cell nuclear antigen (PCNA) were analyzed immunohistochemically in 34 cartilaginous tumor specimens. Eighteen tumors were determined to be chondrosarcoma including 8 Grade 1 tumors, 6 Grade 2 tumors, and 4 Grade 3 tumors. The percentage of CTGF positive and PCNA positive cells was quantified using at least 500 cells. RESULTS: CTGF was expressed in 70.1% of enchondroma cells, 84.0% of Grade 1 chondrosarcoma cells, 53.7% of Grade 2 tumor cells, and 26.8% of Grade 3 tumor cells (rho = -0.501; P = 0.0053). In chondrosarcoma cases, CTGF expression was correlated closely with tumor grade (rho = -0.920; P = 0.0001). There was a strong correlation between PCNA expression and tumor grade (rho = 0.907; P < 0.0001) and a strong negative correlation between CTGF and PCNA expression (rho = -0.493; P = 0.0061). In chondrosarcoma cases, patients with high expression of CTGF (>/= 30%) showed higher overall survival compared with those with low expression (< 30%) (P = 0.004). CONCLUSIONS: The current study revealed a correlation between the histologic grade of chondrosarcoma and prognosis, and the concomitant association between CTGF immunostaining and tumor grade and prognosis. Therefore, immunohistochemical staining with CTGF is a useful procedure for assessing the tumor grade and clinical course in patients with chondrosarcoma.

Adolescent↗

PubMed2000

Increased expression of connective tissue growth factor in fibrotic human liver and in activated hepatic stellate cells.

BACKGROUND/AIMS: Connective tissue growth factor is a recently described mitogenic protein implicated in a variety of fibrotic disorders. Connective tissue growth factor may be a downstream mediator of the pro-fibrotic and mitogenic actions of transforming growth factor-beta, promoting extracellular matrix deposition and fibrogenesis. As transforming growth factor-beta is considered important to the pathogenesis of hepatic fibrosis, we examined the possible contribution of connective tissue growth factor to this process. METHODS: Connective tissue growth factor expression was examined in normal and fibrotic human and rat livers using RT-PCR and ribonuclease protection assays, and in primary cultures of rat hepatic stellate cells by Northern and Western blotting. RESULTS: Ribonuclease protection assays demonstrated connective tissue growth factor mRNA was increased 3-5-fold in human fibrotic liver compared with normal. RT-PCR showed this mRNA was increased in carbon-tetrachloride-treated rat liver. Northern analysis showed connective tissue growth factor mRNA was increasingly expressed during progressive activation of cultured rat hepatic stellate cells. Western analysis confirmed that freshly isolated hepatic stellate cells secreted relatively little connective tissue growth factor compared with hepatic stellate cells activated in culture. Hepatic stellate cells stimulated with transforming growth factor-beta showed increased expression of connective tissue growth factor mRNA and protein. CONCLUSIONS: Connective tissue growth factor mRNA is consistently upregulated in human liver cirrhosis of various aetiologies, supporting a role for this growth factor in hepatic fibrogenesis. Our studies suggest that hepatic stellate cells may be an important source of hepatic connective tissue growth factor in vivo, particularly following stimulation with transforming growth factor-beta.

Animals↗

PubMed2000

Tumor necrosis factor alpha suppresses the induction of connective tissue growth factor by transforming growth factor-beta in normal and scleroderma fibroblasts.

Connective tissue growth factor (CTGF) is overexpressed in a variety of fibrotic disorders, presumably secondary to the activation and production of transforming growth factor-beta (TGF-beta), a key inducer of fibroblast proliferation and matrix synthesis. The CTGF gene promoter has a TGF-beta response element that regulates its expression in fibroblasts but not epithelial cells or lymphocytes. Recent studies have shown that the macrophage-produced cytokine tumor necrosis factor alpha (TNFalpha) is necessary to promote inflammation and to induce genes, such as matrix metalloproteinases, involved with the early stages of wound healing. In this study, we examined the ability of TNFalpha to modulate CTGF gene expression. TNFalpha was found to suppress the TGF-beta-induced expression of CTGF protein in cultured normal fibroblasts. The activity of TNFalpha was blocked by NF-kappaB inhibitors. We showed that sequences between -244 and -166 of the CTGF promoter were necessary for both TGF-beta and TNFalpha to modulate CTGF expression. There was a constitutive expression of CTGF by scleroderma fibroblasts that was increased by TGF-beta treatment. Although TNFalpha was able to repress TGF-beta-induced CTGF and collagen synthesis both in normal and scleroderma skin fibroblasts, fibroblasts cultured from scleroderma patients were more resistant to TNFalpha as TNFalpha was unable to suppress the basal level of CTGF expression in scleroderma fibroblasts. Thus, we suspect that the high level of constitutive CTGF expression in scleroderma fibroblasts and its inability to respond to negative regulatory cytokines may contribute to the excessive scarring of skin and internal organs in patients with scleroderma.

Cell Line↗

PubMed2004

Connective tissue growth factor and renal diseases: some answers, more questions.

PURPOSE OF REVIEW: Connective tissue growth factor (CCN2) has recently received much attention as a possible key determinant of progressive renal fibrosis. However, the mechanism(s) by which this growth factor functions is not known. The purpose of this review is to summarize and discuss the recent findings regarding the possible mechanisms involved. RECENT FINDINGS: Emerging evidence from in-vitro studies of renal cells indicates that connective tissue growth factor is a crucial mediator for transforming growth factor-beta-induced cellular dysfunction, manifest by increased cellular hypertrophy, synthesis of extracellular matrix proteins and their deposition and assembly around the cells. Indeed, recent evidence suggests that the interrelationship between connective tissue growth factor and transforming growth factor-beta is stronger than first thought. While transforming growth factor-beta induces the expression of connective tissue growth factor, the latter plays a key role in both bioactivation of latent transforming growth factor-beta and the promotion of its Smad signalling activity. SUMMARY: Connective tissue growth factor is clearly implicated in the pathogenesis of progressive renal disease. Although there is much to learn about the production, function, and mechanism of action of connective tissue growth factor, some progress has been made in understanding the molecular basis of its relationship with transforming growth factor-beta. Elucidating the signal transduction pathways activated by connective tissue growth factor will also definitely help to clarify other actions of connective tissue growth factor which may be independent of transforming growth factor-beta. Because of the inflammatory and immunosuppressive properties of transforming growth factor-beta, connective tissue growth factor seems to be an attractive alternative therapeutic target for combating renal fibrosis.

Animals↗

PubMed2003

Connective tissue growth factor and its correlation to other growth factors in experimental granulation tissue.

Connective tissue growth factor (CTGF) is upregulated in a variety of fibrotic disorders, probably secondary to the activation and production of transforming growth factor-beta (TGF-beta). We have studied the expression of CTGF in a rat wound-healing model using Northern blot, in situ hybridization, and immunohistochemistry. The expression of CTGF mRNA in Northern blot and immunohistochemistry were correlated to the expression of TGF-beta1 and platelet-derived growth factor (PDGF). Northern hybridization showed the maximum expression of CTGF mRNA on day 14, whereas TGF-beta1 expression was maximal on days 7 and 14 and the time-related changes were smaller than for CTGF. PDGF A and PDGF B mRNA expressions were at maximum on day 14 and on day 21, respectively. In situ hybridization showed that fibroblast-like cells expressed CTGF most intensively, expression declining rapidly after day 14. CTGF mRNA and protein were found in blood vessel cells during the first week. In immunohistochemistry, all growth factors were expressed by fibroblast-like cells, macrophage-like cells, and blood vessels but CTGF-positive cells were fewer and were more restricted on days 5 and 7. These results demonstrate that CTGF expression together with TGF-beta and PDGF are up-regulated in wound healing, and CTGF expression in blood vessels suggests that CTGF is involved in angiogenesis.

Animals↗