Expression of Extracellular Matrix Ligands and Receptors in the Muscular Tissue and Draining Lymph Nodes of mdx Dystrophic Mice

Lagrota-Candido, Jussara; Canella, Isabella; Savino, Wilson; Quirico-Santos, Thereza

doi:10.1006/clim.1999.4749

Cited by 11 publications

(13 citation statements)

References 26 publications

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“…It is not ruled out that marked deposition of LN concomitant with increased percentage of myonecrosis in skeletal muscles of young (6 weeks) mdx males could be promoting inflammatory cell migration. We have previously reported that predominant expression of ECM receptors (a4, a5, and a6 integrins) by infiltrating cells near the foci of myonecrosis, indicate an important role for ECM ligands and receptors in directing adhesion and migration of mononuclear cells in the lesioned muscle and toward local draining lymph nodes (Lagrota-Cândido et al 1999).…”

Section: Discussionmentioning

confidence: 94%

Gender dimorphism influences extracellular matrix expression and regeneration of muscular tissue in mdx dystrophic mice

Salimena

Lagrota-Candido

Quirico-Santos

2000

Histochem Cell Biol

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Mdx mouse, the animal model of Duchenne muscular dystrophy, lacks dystrophin and develops an X-linked recessive inflammatory myopathy characterized by degeneration of skeletal muscle fibers and connective tissue replacement. The present work aimed to assess whether gender dimorphism in mdx mice would influence skeletal muscle pathology at ages corresponding to main histological changes in the microenvironment of muscular tissue: myonecrosis, regeneration, and fibrosis. At the height of myonecrosis (6 weeks postnatal), skeletal muscles of male mdx mice showed increased sarcolemmal permeability, numerous inflammatory foci, and marked deposition of the extracellular matrix components (ECM) type I collagen and laminin. In contrast, age-matched mdx females showed mild ECM deposition, discrete myonecrosis, but increased numbers of regenerating fibers expressing the satellite cell marker NCAM. In contrast ovariectomized mdx females showed decreased numbers of regenerating fibers. Older (24 and 48 weeks postnatal) mdx females showed extensive fibrosis with increased sarcolemmal permeability and marked deposition of ECM components than corresponding males. These results suggest a role for female hormones in the control of myonecrosis probably by promoting regeneration of muscular tissue and mitigating inflammation especially at ages under the critical influence of sex hormones.

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Section: Discussionmentioning

confidence: 94%

Gender dimorphism influences extracellular matrix expression and regeneration of muscular tissue in mdx dystrophic mice

Salimena

Lagrota-Candido

Quirico-Santos

2000

Histochem Cell Biol

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“…In dystrophic muscle, the finding of conserved amino acid sequence in the T-cell receptor (Gussoni et al, 1994), and increased expression of extracellular ma- 881 trix ligands and receptors in the muscular tissue as well as draining lymph nodes (Lagrota-Candido et al, 1999) suggests an important role of T-cells in the pathophysiology of muscular dystrophy. Although cytotoxic lymphocytes have been shown to contribute significantly to apoptosis and regeneration in the mdx mouse (Lagrota-Candido et al, 1999;Spencer et al, 1997), little is known about the contribution of T-lymphocytes to the progressive fibrogenesis that occurs during the repeated degeneration and regeneration of the mdx muscle.Here, we report our finding on fibrogenesis over much of the lifespan of mdx and mdx bred onto the nu/nu background. We find that the absence of T-lymphocytes markedly delayed the onset of collagen deposition in skeletal muscles and some visceral organs of the mdx mouse.…”

mentioning

confidence: 99%

“…In dystrophic muscle, the finding of conserved amino acid sequence in the T-cell receptor (Gussoni et al, 1994), and increased expression of extracellular ma-trix ligands and receptors in the muscular tissue as well as draining lymph nodes (Lagrota-Candido et al, 1999) suggests an important role of T-cells in the pathophysiology of muscular dystrophy.…”

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confidence: 99%

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T-Cell-Dependent Fibrosis in the mdx Dystrophic Mouse

Morrison

Lü

Pastoret

et al. 2000

Laboratory Investigation

111

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SUMMARY:In Duchenne muscular dystrophy patients, the pathological hallmark of the disease, namely, the chronic accumulation of sclerotic scar tissue in the interstitial space of skeletal muscle is attributed to manifestation of secondary pathological processes. Such anomalous generation of matrix protein is thought to be driven by the continuous degeneration and regeneration of muscle both in Duchenne Muscular Dystrophy and in the mdx mouse homolog. We examined mdx and the control strain C57bl/10 mice over a range of ages with respect to the amounts of collagen present in muscles and other organs, finding that the mdx have significantly higher collagen content at later time points in their kidney and lung as well as their muscles. Surprisingly, when we bred the mdx mice on the nu/nu background, the time course of fibrogenesis was modified depending on the tissue and the collagen content was significantly different in age-matched mice. Transplantation of normal thymic tissue into the mdx-nu/nu mice replenished their T-cells and concomitantly altered the collagen content in their tissues to levels comparable with those in immunocompetent mdx mice. This suggests that T-cells play a role in the onset of the fibrotic events that undermines the ability of dystrophic muscle to regenerate. (Lab Invest 2000, 80:881-891). D uchenne muscular dystrophy (DMD) was originally described as a myosclerosis (Duchenne, 1868), in recognition of the conspicuous deposition of collagenous scar tissue within the muscles. Fibrosis entails the excessive and inappropriate deposition of collagenous extracellular matrix. It is a central feature of many chronic diseases because it tends to disrupt and destroy the function of tissue, irrespective of the organ involved, be it kidney, heart, skin or skeletal muscle and is a major cause of suffering and death. It has also been suggested that this connective tissue proliferation may be important in the pathogenesis of the disease (Ionasecu and Ionasecu, 1982). Certainly, in primary myopathies such as Duchenne and congenital muscular dystrophies, striking increases in the levels of matrix proteins are a major histopathological feature (Stephens et al, 1982). In skeletal muscle, in addition to its obvious impact on the mechanical function of the tissue, progressive fibrosis may have widespread effects on a variety of mechanisms, which are crucial to the proper function of this tissue. Thus, the mechanisms of vascular and extravascular perfusion, which are critical for the supply of nutrients and removal of waste products in this metabolically active tissue, are likely to be compromised by the accumulation of dense, sclerotic scar tissue in the interfibre spaces. It has also been suggested that this scar tissue may itself assume a pathogenic role and contribute to the disease progression by interfering with effective muscle regeneration and re-innervation (Lipton, 1979).Experimental investigation of dystrophinopathies has been rendered possible by the advent of authentic animal models of DMD, of whic...

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“…1997). In contrast, enhanced cellularity of draining lymph nodes with significant increase of CD4 + and CD8 + cells expressing ECM receptors was consistently observed during regeneration of muscular tissue and clinical amelioration of the disease in mdx mice (Lagrota‐Candido et al . 1999).…”

mentioning

confidence: 99%

Resolution of skeletal muscle inflammation in mdx dystrophic mouse is accompanied by increased immunoglobulin and interferon‐γ production

Lagrota-Candido

Vasconcellos

Cavalcanti

et al. 2002

Int J Experimental Path

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Summary. Mdx mouse, the animal model of Duchenne muscular dystrophy, develops an X-linked recessive inflammatory myopathy with an apparent sustained capacity for muscle regeneration. We analysed whether changes in the skeletal muscle during myonecrosis and regeneration would correlate with functional alterations in peripheral lymphoid tissues. Here we show that during the height of myonecrosis, mdx mice display marked atrophy of peripheral lymph nodes and extensive muscle inflammation. In contrast, enlargement of draining lymph nodes with accumulation of CD4 CD44 , CD4 CD25 , CD8 CD44 T lymphocytes and type-2 B cells was consistently observed during amelioration of the muscle lesion. In addition, regeneration of the muscular tissue was accompanied by concomitant increase of immunoglobulin-secreting cells in regional lymph nodes and bone marrow. Double immunolabelling analysis revealed intense B cell proliferation and formation of germinal centre in the follicles of dystrophic regional lymph nodes. Furthermore, lymph node cells produced large amounts of IFN-g but not IL-4, IL-6 or IL-10 after in vitro mitogen stimulation with Concanavalin A. As these alterations occurred mainly during the recovery period, we suggested that local activation of the immune system could be an influence which mitigates the myonecrosis of muscular tissue in the mdx dystrophic mouse.

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Expression of Extracellular Matrix Ligands and Receptors in the Muscular Tissue and Draining Lymph Nodes of mdx Dystrophic Mice

Cited by 11 publications

References 26 publications

Gender dimorphism influences extracellular matrix expression and regeneration of muscular tissue in mdx dystrophic mice

Gender dimorphism influences extracellular matrix expression and regeneration of muscular tissue in mdx dystrophic mice

T-Cell-Dependent Fibrosis in the mdx Dystrophic Mouse

Resolution of skeletal muscle inflammation in mdx dystrophic mouse is accompanied by increased immunoglobulin and interferon‐γ production

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