Activation of Tissue Inhibitor of Metalloproteinases-3 (TIMP-3) mRNA Expression in Scleroderma Skin Fibroblasts

Mattila, Laura; Airola, Kristiina; Ahonen, Matti; Hietarinta, M.; Black, Carol M.; Saarialho–Kere, Ulpu; Kähäri, Veli‐Matti

doi:10.1046/j.1523-1747.1998.00138.x

Cited by 61 publications

(39 citation statements)

References 50 publications

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“…To our knowledge, there are no data on TIMP-3 in other cutaneous disorders associated with apoptosis, such as lichen planus or erythema multiforme. The finding of TIMP-3 up-regulation in the stroma of high-grade and late graft-versus-host disease is in accordance with our earlier results that TIMP-3 is also overexpressed in other skin disorders associated with severe dermal fibrosis, such as scleroderma (12).…”

Section: Discussionsupporting

confidence: 92%

“…Lack of MMP expression and up-regulation of dermal MMP inhibitors may lead to the accumulation of extracellular matrix and fibrosis, both important histological findings in chronic cutaneous graft-versus-host disease. In fact, we have previously demonstrated TGF-␤-mediated activation of TIMP-3 in sclerodermatous skin fibroblasts in culture (12).…”

Section: Discussionmentioning

confidence: 91%

“…Matrix metalloproteinases and TIMPs have previously been implicated in the pathomechanism of several inflammatory disorders of the skin and intestine, such as celiac disease, ulcerative colitis, and Crohn's disease (9,10), as well as granulomatous skin disorders, lichen planus, and scleroderma (11)(12)(13)(14). Several studies have shown the expression of various MMPs, particularly MMPs -1, -3, -12 and -14, in intestinal ulcers of patients with inflammatory bowel disease (9,10,15,16).…”

mentioning

confidence: 99%

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Overexpression of Tissue Inhibitor of Metalloproteinases-3 in Intestinal and Cutaneous Lesions of Graft-versus-Host Disease

Salmela

Karjalainen–Lindsberg

Jeskanen

et al. 2003

Modern Pathology

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Matrix metalloproteinases (MMPs) have been implicated in the pathobiology of various T-cell-mediated inflammatory disorders of the intestine and skin. Their synthetic inhibitor has been shown to prevent lethal acute graft-versus-host disease in animal models. We intended to determine the expression of MMPs 1, 3, 7, 9, 10, 12, and 19 and tissue inhibitors of metalloproteinases (TIMPs) 1 and 3 in intestinal and cutaneous lesions of patients suffering from graft-versus-host disease after bone marrow transplantation. In situ hybridizations for MMPs 1, 3, 7, 10, and 12 as well as TIMPs 1 and 3 were performed using 35 S-labeled cRNA probes on intestinal (n ‫؍‬ 13) and cutaneous specimens (n ‫؍‬ 9) from patients with graft-versus-host disease. Immunohistochemical stainings were carried out to localize MMP-9, MMP-19, TIMP-3, and TGF-␤1 proteins, and TUNEL staining, to detect apoptotic cells. TIMP-3 mRNA and protein were detected in cutaneous lesions in areas with vacuolar degeneration of the basal epidermal layer in all skin samples, and they colocalized with apoptotic keratinocytes and partly with staining for TGF-␤. None of the MMPs examined were overexpressed in skin lesions. Signals for MMP-1 and MMP-3 mRNA was found in 10/13 and 5/13 intestinal biopsies, respectively. In the gut, MMP-19 -positive epithelial cells, particularly in the crypts, were found in 10/13 samples. Expression of MMPs 7, 9, 10, and 12 was absent or very low. TIMPs 1 and 3 were expressed by stromal cells in 12/13 and 10/13 gut samples, respectively. Whereas TIMP-1 was expressed particularly by subepithelial cells where epithelium had shed away, TIMP-3 was detected in deeper areas. We conclude that MMPs are differentially regulated in the skin and gut lesions of graft-versus-host disease. In agreement with previous data on cancer cells, TIMP-3, induced by TGF-␤1, may contribute to the apoptosis of keratinocytes in cutaneous graftversus-host disease lesions, leading to typical histopathological changes. We also conclude that MMPs play a less important role as effector molecules in intestinal graft-versus-host disease than in celiac or inflammatory bowel disease.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

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Overexpression of Tissue Inhibitor of Metalloproteinases-3 in Intestinal and Cutaneous Lesions of Graft-versus-Host Disease

Salmela

Karjalainen–Lindsberg

Jeskanen

et al. 2003

Modern Pathology

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“…TIMP-3 regulation in tenocytes has not been examined to our knowledge, but in other cell types its expression, like CTGF and ADAMTS-1, is induced by TGFb both in vitro and in clinical scenarios involving fibrosis. 21,22 It has been postulated that elevated TIMP-3 expression in fibrotic conditions may contribute to the development of excessive scarring by inhibiting the turnover of reparative collagen in healing wounds. 22 In summary, SC injection significantly influenced several TGFb-induced tendon genes, and further work will be required to explore the biology of these particular pathways.…”

Section: Gene Expression Changes Mediated By Mast Cell Degranulationmentioning

confidence: 99%

Sodium cromolyn reduces expression of CTGF, ADAMTS1, and TIMP3 and modulates post‐injury patellar tendon morphology

Sharma

Abraham

Sampaio

et al. 2010

Journal Orthopaedic Research

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The purpose of this study was to determine whether administration of a mast cell inhibitor (sodium cromolyn, SC) would influence tendon repair and extracellular matrix gene expression following acute injury. CD1 mouse patellar tendons were unilaterally injured and mast cell prevalence was determined. The effect of SC injection on tendon hypercellularity, cross-sectional area, collagen organization, and expression of extracellular matrix-related genes was examined. Mast cell prevalence was markedly increased in injured patellar tendons ( p ¼ 0.009), especially at 8 weeks post-injury ( p ¼ 0.025). SC injection increased collagen organization compared to uninjected animals at 4 weeks and attenuated the development of tendon hypercellularity and tendon thickening post-injury. Expression of CTGF, ADAMTS1, and TIMP3 in injured tendon was reduced in the SC group. SC injections moderated the structural alterations of healing tendon in association with downregulation of several genes associated with tendon fibrosis. This work corroborates previous findings pointing to a role of mast cells in tendon repair. ß

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“…In addition, elevated serum TIMP-1 levels have been shown to correlate with disease activity and the early phase in SSc patients [29,30]. Activated skin fibroblasts were reported to express elevated levels of TIMP-3 mRNA in culture and in vivo [31]. However, cultured fibroblasts from patients with early SSc exhibited higher levels of MMP-1, MMP-3 and TIMP-1 mRNA expression than those from normal controls, while TIMP-1 mRNA expression remained increased, but MMP-1 and MMP-3 mRNA expression was decreased in fibroblasts from patients with mid-stage SSc [6].…”

Section: Discussionmentioning

confidence: 99%

Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis

Nishijima

Hayakawa

Matsushita

et al. 2004

Clinical and Experimental Immunology

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SUMMARY Systemic sclerosis (SSc) is characterized by multi-organ fibrosis with an autoimmune background. Although autoantibodies are detected frequently in SSc patients, the role of autoantibody in the development of fibrosis remains unknown. Connective tissue homeostasis is a balance between the synthesis and degradation of the extracellular matrix (ECM); ECM degradation is regulated mainly by matrix metalloproteinases (MMPs). Anti-MMP-1 antibody is suggested to inhibit MMP-1 and be involved in the development of the fibrosis in SSc. However, the accumulation of various ECM components in the tissue of SSc cannot be explained by the anti-MMP-1 antibody alone. In this study, we examined the presence or levels of antibody to MMP-3, a protein which degrades various ECM components relevant to SSc fibrosis. Enzyme-linked immunosorbent assay (ELISA) using human recombinant MMP-3 revealed that IgG anti-MMP-3 autoantibody levels were elevated significantly in the sera from SSc patients, but not in patients with active systemic lupus erythematosus or dermatomyositis. IgG and IgM anti-MMP-3 antibody levels were significantly higher in diffuse cutaneous SSc, a severe form, than those in limited cutaneous SSc. Consistently, IgG anti-MMP-3 antibody levels correlated significantly with fibrosis of the skin, lung and renal blood vessels. The presence of IgG anti-MMP-3 autoantibody in sera from SSc patients was confirmed by immunoblotting analysis. Remarkably, MMP-3 activity was inhibited by IgG anti-MMP-3 antibody. These results suggest that anti-MMP-3 antibody is a serological marker that reflects the severity of SSc and also suggest that it may contribute to the development of fibrosis by inhibiting MMP-3 activity and reducing the ECM turnover.

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Activation of Tissue Inhibitor of Metalloproteinases-3 (TIMP-3) mRNA Expression in Scleroderma Skin Fibroblasts

Cited by 61 publications

References 50 publications

Overexpression of Tissue Inhibitor of Metalloproteinases-3 in Intestinal and Cutaneous Lesions of Graft-versus-Host Disease

Overexpression of Tissue Inhibitor of Metalloproteinases-3 in Intestinal and Cutaneous Lesions of Graft-versus-Host Disease

Sodium cromolyn reduces expression of CTGF, ADAMTS1, and TIMP3 and modulates post‐injury patellar tendon morphology

Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis

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