| 1. |
- Bergström, Ulf, et al.
(författare)
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Effects of adalimumab treatment on endothelial cell activation markers in the skeletal muscle of patients with rheumatoid arthritis.
- 2014
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Ingår i: Clinical and Experimental Rheumatology. - 1593-098X .- 0392-856X. ; 32:6, s. 883-890
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Tidskriftsartikel (refereegranskat)abstract
- Patients with rheumatoid arthritis (RA), particularly those with severe disease, have increased risk of cardiovascular disease (CVD). Previous studies suggest that endothelial cell activation may contribute to this co-morbidity, and that treatment with tumour necrosis factor (TNF) inhibitors could reduce the risk of CVD in these patients. The aim of this study was to investigate endothelial cell activation markers in muscle tissue of patients after adalimumab treatment.
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| 2. |
- Grundtman, Cecilia
(författare)
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Pathogenic mechanisms in idiopathic inflammatory myopathies
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Idiopathic inflammatory myopathies (IIMs) are chronic inflammatory disorders characterized by muscle weakness, by low muscle endurance, and by inflammation in skeletal muscle tissue. The pathogenesis and etiology of these conditions are yet not fully understood and several different mechanisms are likely to be involved. The most characteristic histopathological finding is the presence of inflammatory cell infiltrates in muscle tissue together with degenerating and regenerating muscle fibers. The main goal of this thesis was to increase our knowledge of the pathogenic mechanisms in IIMs, in particular how the immune reactions could cause impaired muscle performance. We characterized IIM patients and healthy subjects through muscle biopsies in different phases of disease, we performed detailed studies on the cellular level and in an animal model of IIMs, and correlated our results from in vivo studies with in vitro models. Several new observations were made in this thesis. Firstly, we found a reduced number and morphologically changed capillaries in patients with short disease duration and without inflammatory cell infiltrates in muscle tissue. This finding correlated to an upregulated expression of the aniogenetic factor vascular endothelium growth factor (VEGF) in muscle fibers. These observations may suggest that local muscle hypoxia could be a contributing factor to the impaired muscle function seen in patients. Secondly, we found that the pro-inflammatory cytokines interleukin (IL)-1 and high mobility group box chromosomal protein (HMGB)-1 were consistently expressed in muscle tissue of patients with IIMs not only in inflammatory cells but also in endothelial cells and the nuclei of muscle fibers. The expression of IL-1 and their receptors in muscle nuclei indicate that IL-1 could possess direct effects on muscle fibers and affect muscle fiber metabolism and function. In addition, HMGB-1 was found to reversibly induce major histocompatibility complex (MHC) class I expression on muscle fibers and irreversibly impair Ca2+ release from the sarcoplasmic reticulum during induction of fatigue, indicating a direct effect of HMGB-1 on generation of muscle force. Moreover, the expression of MHC class I in muscle fibers, which are a pathological finding in patients with IIMs, led to a specific muscle force reduction in an animal model. In this model the reduced force was associated with decreased cross-sectional area in fast-twitch muscle whereas it was due to a decrease in the intrinsic force-generating capacity in slow-twitch muscles, indicating that MHC class I upregulation affects muscle fiber contractility with differential effects depending on muscle fiber properties. In summary, we have identified different molecular pathways that might play a pathogenic role in these disorders and how they can lead to low muscle performance. These include tissue hypoxia as a consequence of a distorted microcirculation in skeletal muscle tissue as well as direct and indirect effects of the pro-inflammatory cytokines IL-1 and HMGB-1 on muscle fiber contractility. Thus, it is likely that both immune and non-immune-mediated pathways contribute to the impaired muscle function seen in IIMs and this needs to be recognized in the development of new therapeutic modalities.
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| 3. |
- Nader, Gustavo A., et al.
(författare)
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A Longitudinal, Integrated, Clinical, Histological and mRNA Profiling Study of Resistance Exercise in Myositis
- 2010
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Ingår i: Molecular Medicine. - : Springer Science and Business Media LLC. - 1076-1551 .- 1528-3658. ; 16:11-12, s. 455-464
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Tidskriftsartikel (refereegranskat)abstract
- Polymyositis and dermatomyositis are orphan, chronic skeletal muscle disorders characterized by weakness, infiltrations by mononuclear inflammatory cells, and fibrosis. Until recently, patients were advised to refrain from physical activity because of fears of exacerbation of muscle inflammation. However, recent studies have shown that moderate exercise training in combination with immunosuppressive drugs can improve muscle performance. Despite the positive effects of exercise training, the molecular mechanisms underlying the exercise-associated clinical improvements remain poorly understood. The present study was designed to define, at the molecular level, the effects of resistance exercise training on muscle performance and disease progression in myositis patients. We evaluated changes in muscle strength, histology and genome-wide mRNA profiles to determine the beneficial effects of exercise and determine the possible molecular changes associated with improved muscle performance. A total of 8 myositis patients underwent a 7-wk resistance exercise training program that resulted in improved muscle strength and increased maximal oxygen uptake (VO2max). Training also resulted in marked reductions in gene expression, reflecting reductions in proinflammatory and profibrotic gene networks, changes that were also accompanied by a reduction in tissue fibrosis. Consistent with the exercise-associated increase in VO2max, a subset of transcripts was associated with a shift toward oxidative metabolism. The changes in gene expression reported in the present study are in agreement with the performance improvements induced by exercise and suggest that resistance exercise training can induce a reduction in inflammation and fibrosis in skeletal muscle.
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| 4. |
- Sundberg, Erik, et al.
(författare)
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Systemic TNF blockade does not modulate synovial expression of the pro-inflammatory mediator HMGB1 in rheumatoid arthritis patients : a prospective clinical study
- 2008
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 10:2, s. R33-
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Tidskriftsartikel (refereegranskat)abstract
- Introduction High-mobility group box chromosomal protein 1 (HMGB1) has recently been identified as an endogenous mediator of arthritis. TNF and IL-1 beta, pivotal cytokines in arthritis pathogenesis, both have the ability to induce the release of HMGB1 from myeloid and dendritic cells. It was, therefore, decided to investigate whether treatment based on TNF blockade in rheumatoid arthritis (RA) affects the expression of synovial HMGB1. Methods Repeated arthroscopy-guided sampling of synovial tissue was performed in nine patients with RA before and nine weeks after initiation of anti-TNF mAb (infliximab) therapy. Synovial biopsy specimens were analysed for HMGB1 protein by immunohistochemical staining and for HMGB1 mRNA expression by real-time reverse transcriptase PCR (RT-PCR). Statistical evaluations were based on Wilcoxon's signed rank tests or Spearman rank sum tests. Results Aberrant, extranuclear HMGB1 and constitutive nuclear HMGB1 expression, with histological signs of inflammation, were evident in all biopsies obtained before infliximab therapy. Signs of inflammation were still evident in the second biopsies obtained nine weeks after initiation of infliximab therapy. The cytoplasmic and extracellular expression of HMGB1 decreased in five patients, remained unchanged in one patient and increased in three patients, making the overall change in HMGB1 protein expression not significant. No correlation between the clinical response, as measured by disease activity score calculated for 28 joints (DAS28) or the American College of Rheumatology response criteria (ACR 20, 50, and 70), and the direction of change of HMGB1 expression in individual patients could be discerned. In addition, infliximab therapy did not alter HMGB1 mRNA synthesis. Conclusion Pro-inflammatory HMGB1 expression during rheumatoid synovitis was not consistently influenced by TNF-blocking therapy with infliximab. This suggests that TNF is not the main inducer of extranuclear HMGB1 during synovitis and that HMGB1 may represent a TNF-independent molecule that could be considered as a possible target for future therapeutic intervention in RA.
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| 5. |
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| 6. |
- Yamada, Takashi, et al.
(författare)
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Impaired Myofibrillar Function in the Soleus Muscle of Mice With Collagen-Induced Arthritis
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:11, s. 3280-3289
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Progressive muscle weakness is a common feature in patients with rheumatoid arthritis (RA). However, little is known about whether the intrinsic contractile properties of muscle fibers are affected in RA. This study was undertaken to investigate muscle contractility and the myoplasmic free Ca2+ concentration ([Ca2+](i)) in the soleus, a major postural muscle, in mice with collagen-induced arthritis (CIA). Methods. Muscle contractility and [Ca2+](i) were assessed in whole muscle and intact single-fiber preparations, respectively. The underlying mechanisms of contractile dysfunction were assessed by investigating redox modifications using Western blotting and antibodies against nitric oxide synthase (NOS), superoxide dismutase (SOD), 3-nitrotyrosine (3-NT), carbonyl, malondialdehyde (MDA), and S-nitrosocysteine (SNO-Cys). Results. The tetanic force per cross-sectional area was markedly decreased in the soleus muscle of mice with CIA, and the change was not due to a decrease in the amplitude of [Ca2+](i) transients. The reduction in force production was accompanied by slowing of the twitch contraction and relaxation and a decrease in the maximum shortening velocity. Immunoblot analyses showed a marked increase in neuronal NOS expression but not in inducible or endothelial NOS expression, which, together with the observed decrease in SOD2 expression, favors peroxynitrite formation. These changes were accompanied by increased 3-NT, carbonyl, and MDA adducts content in myofibrillar proteins from the muscles of mice with CIA. Moreover, there was a significant increase in SNO-Cys content in myosin heavy-chain and troponin I myofibrillar proteins from the soleus muscle of mice with CIA. Conclusion. These findings show impaired contractile function in the soleus muscle of mice with CIA and suggest that this abnormality is due to peroxynitrite-induced modifications in myofibrillar proteins.
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