Expression of Matrix Metalloproteinases in Cyclosporin‐Treated Gingival Fibroblasts Is Regulated by Transforming Growth Factor (TGF)‐β1 Autocrine Stimulation

Cotrim, P.; Andrade, Cléverton Roberto de; Martelli‐Júnior, Hercílio; Graner, Edgard; Sauk, John J.; Coletta, Ricardo D.

doi:10.1902/jop.2002.73.11.1313

Cited by 52 publications

(67 citation statements)

References 55 publications

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“…The rat model associated with primary cultures of human gingival fibroblast treated with CyA was chosen on the basis of our previous experiments to mimic the CyA-induced gingival overgrowth seen in humans. 5,6,12 The main finding of the present study was that myofibroblast transdifferentiation is not induced by CyA, even with CyA stimulating TGF-β1 expression. Furthermore, we were able to demonstrate that CTGF expression levels were unaffected by CyA, suggesting a reason for the lack of myofibroblast transdifferentiation.…”

Section: Discussionmentioning

confidence: 51%

“…7,8,23,24 The regulatory cytokine TGF-β1 has been traditionally considered an inducer of the myofibroblast phenotypes both in vivo and in vitro. 25 Since CyA induces gingival overgrowth in the presence of fibroblasts characterized by the synthesis of elevated levels of TGF-β1, 5,6 we evaluated the effects of CyA on transdifferentiation of gingival fibroblasts to myofibroblasts. The rat model associated with primary cultures of human gingival fibroblast treated with CyA was chosen on the basis of our previous experiments to mimic the CyA-induced gingival overgrowth seen in humans.…”

Section: Discussionmentioning

confidence: 99%

“…In the gingiva as well as in the kidneys, liver and heart, CyA is known to promote collagen deposition. 4 CyA induces transforming growth factor-beta1 (TGF-β1) expression by human gingival fibroblasts, 5,6 which is, in association with an elevated synthesis of collagen, an intrinsic characteristic of myofibroblasts. 7 Myofibroblasts are characterized by expression of the specific isoform α of smooth muscle actin (α-SMA) and, when activated, synthesize el-evated levels of extracellular matrix proteins.…”

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confidence: 99%

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Cyclosporin A-induced gingival overgrowth is not associated with myofibroblast transdifferentiation

et al. 2010

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Cyclosporin A (CyA) induces gingival overgrowth via its stimulatory effects on expression of transforming growth factor-beta1 (TGF-β1) and collagen. It is not known whether CyA has a direct effect on gingival fibroblasts or induces its effect indirectly via stimulation of myofibroblast transdifferentiation. The present study was undertaken to examine the in vivo and in vitro effect of CyA on myofibroblast transdifferentiation. Rats were treated for 60 days with a daily subcutaneous injection of CyA, and the gingival overgrowth tissue was analyzed by immunohistochemistry. In vitro, fibroblasts from normal gingiva (NG) were cultured in the presence of different concentrations of CyA, and subjected to semi-quantitative reverse transcriptase-polymerase chain reaction and western blot. Although CyA treatment stimulated TGF-β1 expression by NG fibroblasts, it lacked to induce expression and production of isoform α of smooth muscle actin (α-SMA), the specific myofibroblast marker. The expression levels of connective tissue growth factor (CTGF), which has been considered a key molecule to promote the transdifferentiation of myofibroblasts via TGF-β1 activation, were unaffected by CyA. Our results demonstrate that CyA-induced gingival overgrowth is not associated with activation of myofibroblast transdifferentiation, since CyA is not capable to increase CTGF expression.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Cyclosporin A-induced gingival overgrowth is not associated with myofibroblast transdifferentiation

et al. 2010

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“…Previous studies have showed that TGF-β1 may play a role in drug-induced GO [19][20][21][22]. Recent studies support the theory that CsA increases the level of TGF-β1 in GCF samples from CsA-treated patients [23].…”

Section: Introductionmentioning

confidence: 64%

Local Inflammation Exacerbates Cyclosporine A-Induced Gingival Overgrowth in Rats

Guo

Wang²,

Yao

et al. 2008

Inflammation

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Gingival overgrowth (GO) is a common side effect of long-term cyclosporine A (CsA) treatment. The risk factors appraised include drug interactions with calcium channel blockers, age, cyclosporine dose, dental bacterial plaque, duration of treatment, and genetic predisposition. The relationship and mechanism between GO and local inflammation caused by dental bacterial plaque have not been clearly defined. This research was carried out to investigate the histomorphometrical alterations and serum levels of transforming growth factor beta1 (TGF-beta1) in CsA-induced GO with or without local inflammation. Thirty-four male Sprague-Dawley rats were divided into 4 groups: Group I (control); Group II (ligation); Group III (CsA); Group IV (ligation and CsA). After 9 weeks the rats were sacrificed. The morphological examination was made and the histological changes with hematoxylin and eosin (HE) staining were observed. TGF-beta1 levels in serum were detected by enzyme-linked immunosorbent assay (ELISA). We report here that obvious GO are found in Group III and Group IV after CsA treatment, especially those rats with existed gingivitis presented an aggravation of GO. TGF-beta1 levels in CsA-exposed groups were significantly higher than untreated groups, but ligation did not affect TGF-beta1 level. These findings suggest that CsA-induced GO can be exacerbated by local inflammation. TGF-beta1 may be a key factor for the development of GO.

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“…Although the present experiments cannot determine whether angiotensin II regulates MMP-2 and MT1-MMP expression directly or indirectly through TGF-␤ 1 , there is a recent report showing the negative regulation of MMP-1 and MMP-2 by TGF-␤ 1 in human gingival fibroblasts. 34 In conclusion, increases in local generation of angiotensin II and expression of AT 1 receptors in coronary vessels observed at the insulin-resistant stage of NIDDM in OLETF rats 18 appear to modulate coronary expression of ECMrelated molecules and lead to coronary matrix remodeling, possibly associated with overproduction of TGF-␤ 1 . This …”

Section: Discussionmentioning

confidence: 85%

Role of Angiotensin II in Altered Expression of Molecules Responsible for Coronary Matrix Remodeling in Insulin-Resistant Diabetic Rats

Jesmin

Sakuma

Hattori

et al. 2003

ATVB

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Objective-Coronary remodeling based on collagen abnormalities in diabetes might be associated with potential interactions between the matrix metalloproteinase (MMP) system, which regulates extracellular matrix turnover, and the fibrinolytic system, which is involved in the fibrin degradation process. We characterized the profiles of the MMP and fibrinolytic systems in insulin-resistant diabetic rat hearts. Methods and Results-By immunohistochemistry and in situ hybridization, transforming growth factor-␤ 1 (TGF-␤ 1 ) expression increased in coronary vessels, the perivascular area, and cardiomyocytes in diabetic rat hearts. Increased expression of plasminogen activator inhibitor-1 (PAI-1) in coronary vessels and the perivascular area was evident in diabetic hearts. In contrast, diabetic hearts exhibited reduced activity and expression of MMP-2 and decreased expression of membrane type-1 MMP (MT1-MMP). Both intravascular and extravascular collagen type I and III immunoreactivity and fibrin deposition were seen in diabetic coronary vessels. These alterations were reversed to nondiabetic levels by the angiotensin II type 1 receptor blocker candesartan, which prevented the development of perivascular fibrosis observed after Masson's trichrome staining. Key Words: matrix remodeling Ⅲ matrix metalloproteinases Ⅲ diabetes Ⅲ plasminogen activator inhibitor-1 Ⅲ angiotensin II C ollagen in the normal adult heart serves several important functions, which include providing a supportive structural lattice for cardiomyocytes and coronary vessels and connecting individual myocytes and myofibrillar bundles to integrate individual cardiac contractions. However, a disproportionate increase in collagen accretion or collagen resorption from normal levels can cause defects in the function and supporting structural lattice of the heart. It has been widely known that diabetes is associated with alterations in extracellular matrix (ECM) turnover and regulation. 1 Pathologic remodeling characterized by ECM deposition might contribute to cardiovascular complications that are the leading cause of morbidity and mortality in diabetic patients. 2 Alteration in diastolic filling of the left ventricle (LV) associated with reciprocal changes in the LV collagen gene and accumulation of cardiac collagen in diabetic rats 3,4 suggest that increased interstitial cardiac collagen might cause cardiac fibrosis and result in greater LV stiffness and decreased LV wall compliance, thus leading to diastolic dysfunction and eventual heart failure in diabetes. Conclusions-InClearly, an imbalance between ECM production and degradation must underlie the process of ECM expansion, but these dynamics in the diabetic heart are poorly understood. Matrix metalloproteinases (MMPs) are primarily responsible for the breakdown of ECM proteins such as collagen and elastin, and their activity is tightly regulated by tissue inhibitors of MMPs (TIMPs). 5,6 Recent experimental evidence indicates that expression of MMP-2 and MMP-9 is altered in renal tissues and vasculature fr...

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Expression of Matrix Metalloproteinases in Cyclosporin‐Treated Gingival Fibroblasts Is Regulated by Transforming Growth Factor (TGF)‐β1 Autocrine Stimulation

Abstract: The data presented here suggest that TGF-beta1 in an autocrine fashion may contribute to a reduction of proteolytic activity of human gingival fibroblasts in CsA-induced gingival overgrowth, which favors the accumulation of extracellular matrix.

Cited by 52 publications

References 55 publications

Cyclosporin A-induced gingival overgrowth is not associated with myofibroblast transdifferentiation

Cyclosporin A-induced gingival overgrowth is not associated with myofibroblast transdifferentiation

Local Inflammation Exacerbates Cyclosporine A-Induced Gingival Overgrowth in Rats

Role of Angiotensin II in Altered Expression of Molecules Responsible for Coronary Matrix Remodeling in Insulin-Resistant Diabetic Rats

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