Reduced muscle necrosis and long-term benefits in dystrophic mdx mice after cV1q (blockade of TNF) treatment

Radley‐Crabb, Hannah G.; Davies, Marilyn; Grounds, Miranda D.

doi:10.1016/j.nmd.2007.11.002

Cited by 82 publications

(71 citation statements)

References 51 publications

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“…Several previous studies have demonstrated that experimental interventions that reduce subsets of immune cells in vivo can reduce muscle pathology in the mdx mouse (1,2,8,9). Depletion of CD8 + T cells (10), CD4 + T cells (1), macrophages (2), eosinophils (6), neutrophils (3), and TNF (11)(12)(13)(14)(15) or treatment with immunosuppressants (9,14) have all been shown to improve pathogenic features of the disease in mouse models. These studies support a role for the immune system as an exacerbating factor that promotes muscle pathology in the muscular dystrophies and suggest that interventions that target these invading cells might provide therapeutic benefit.…”

Section: Introductionmentioning

confidence: 99%

Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-β

Vetrone¹,

Montecino‐Rodriguez²,

Kudryashova³

et al. 2009

J. Clin. Invest.

265

309

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Duchenne muscular dystrophy (DMD) is an X-linked, degenerative muscle disease that is exacerbated by secondary inflammation. Here, we characterized the immunological milieu of dystrophic muscle in mdx mice, a model of DMD, to identify potential therapeutic targets. We identified a specific subpopulation of cells expressing the Vβ8.1/8.2 TCR that is predominant among TCR-β + T cells. These cells expressed high levels of osteopontin (OPN), a cytokine that promotes immune cell migration and survival. Elevated OPN levels correlated with the dystrophic process, since OPN was substantially elevated in the serum of mdx mice and muscle biopsies after disease onset. Muscle biopsies from individuals with DMD also had elevated OPN levels. To test the role of OPN in mdx muscle, mice lacking both OPN and dystrophin were generated and termed doublemutant mice (DMM mice). Reduced infiltration of NKT-like cells and neutrophils was observed in the muscle of DMM mice, supporting an immunomodulatory role for OPN in mdx muscle. Concomitantly, an increase in CD4 + and FoxP3 + Tregs was also observed in DMM muscle, which also showed reduced levels of TGF-β, a known fibrosis mediator. These inflammatory changes correlated with increased strength and reduced diaphragm and cardiac fibrosis. These studies suggest that OPN may be a promising therapeutic target for reducing inflammation and fibrosis in individuals with DMD.

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Section: Introductionmentioning

confidence: 99%

Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-β

Vetrone¹,

Montecino‐Rodriguez²,

Kudryashova³

et al. 2009

J. Clin. Invest.

265

309

View full text Add to dashboard Cite

show abstract

“…7 Pharmaceutical and nutritional interventions are currently being investigated as potential treatments for the disease, aimed at slowing the inflammatory response that precedes the loss of functional muscle tissue. [8][9][10][11] The conventional method for assessing the effectiveness of these treatments is based on animal models of the disease, using the morphological analysis of histological sections of excised tissue samples under light microscopy. 12 While extremely valuable for evaluating the efficacy of potential treatments, this method necessitates the sacrifice of large numbers of animals.…”

Section: Introductionmentioning

confidence: 99%

Identification of muscle necrosis in the mdx mouse model of Duchenne muscular dystrophy using three-dimensional optical coherence tomography

et al. 2011

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Abstract. Three-dimensional optical coherence tomography (3D-OCT) was used to image the structure and pathology of skeletal muscle tissue from the treadmill-exercised mdx mouse model of human Duchenne muscular dystrophy. Optical coherence tomography (OCT) images of excised muscle samples were compared with coregistered hematoxylin and eosin-stained and Evans blue dye fluorescence histology. We show, for the first time, structural 3D-OCT images of skeletal muscle dystropathology well correlated with co-located histology. OCT could identify morphological features of interest and necrotic lesions within the muscle tissue samples based on intrinsic optical contrast. These findings demonstrate the utility of 3D-OCT for the evaluation of small-animal skeletal muscle morphology and pathology, particularly for studies of mouse models of muscular dystrophy.C 2011 Society of Photo-Optical Instrumentation Engineers (SPIE).

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“…The area of degenerating/regenerating (basophilic) muscle fibers was calculated relative to each total area, and the number of lesions of basophilic muscle fibers was counted for the entire muscle cross-sectional area, as previously described. 18 Briefly, histological analysis was carried out on whole muscle cross-sections. Muscle morphology was drawn using Image Pro Plus 4.5.1 software (Media Cybernetics, Silver Spring, MD, USA), and specific histological features were measured as a percentage (area) of the whole muscle section.…”

Section: Histochemical and Immunofluorescent Staining Analysis Of Musmentioning

confidence: 99%

Early inhibition of tumor necrosis factor‐α and interleukin‐6 in muscle tissue as a therapy for dystrophinopathy in mdx mice

Arahata

Ohyagi

Iinuma

et al. 2014

Clinical & Exp Neuroim

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Objective Pro-inflammatory cytokines can exacerbate muscle fiber damage in dystrophinopathy. The aim of the present study was to identify cytokine/ chemokine alterations in the muscle tissues of mdx mice, a model of dystrophinopathy, and the beneficial effects of anti-proinflammatory cytokine therapy. Methods A total of 23 cytokines and chemokines were quantitatively measured in muscle tissues from mdx mice by fluorescent bead-based immunoassay. The mdx mice were treated with anti-tumor necrosis factor-a (TNF-a) and anti-interleukin-6 (IL-6) drugs, and their physical condition was evaluated by Rotarod and muscle damage by histopathological analysis. Results Levels of TNF-a and IL-6 were elevated at 14 days (P14), before a transient increase of macrophage and neutrophil-activating pro-inflammatory cytokines/chemokines, such as C-C motif ligand 2 (CCL2), CCL4 and KC (mouse C-X-C motif ligand 8 homolog), at P20. Administration of an anti-TNF-a drug (etanercept) and an anti-IL-6 receptor antibody (MR16-1) from P7 improved physical performance, and reduced both the area of basophilic fibers that indicated degenerating/regenerating fibers and CD68-positive macrophage infiltration. Initiating therapy at P7 inhibited the elevation of CCL2, CCL4 and KC more effectively than at P13. Conclusions The early administration of anti-TNF-a and anti-IL-6 drugs attenuated muscle fiber degeneration in a mouse model of dystrophinopathy.

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Reduced muscle necrosis and long-term benefits in dystrophic mdx mice after cV1q (blockade of TNF) treatment

Cited by 82 publications

References 51 publications

Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-β

Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-β

Identification of muscle necrosis in the mdx mouse model of Duchenne muscular dystrophy using three-dimensional optical coherence tomography

Early inhibition of tumor necrosis factor‐α and interleukin‐6 in muscle tissue as a therapy for dystrophinopathy in mdx mice

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