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ABSTRACT: OBJECTIVE: To test whether inhibition of sclerostin by a targeted monoclonal antibody (Scl-Ab) protects from bone and cartilage damage in inflammatory arthritis. Sclerostin is a potent inhibitor of bone formation and may be responsible for the low level of bone repair in patients with rheumatoid arthritis. METHODS: Human tumour necrosis factor transgenic mice (hTNFtg mice) developing inflammatory arthritis and local and bone loss were administered either vehicle, anti-TNF antibody, Scl-Ab, or a combination of both agents. Inflammation, systemic and periarticular bone loss, bone erosion and cartilage damage were evaluated at baseline (week 8) and after 3 weeks of treatment by clinical assessment, micro-CT and histology. RESULTS: Scl-Ab did not affect joint swelling or synovitis. Systemic bone loss in the spine and periarticular bone loss in the proximal tibia were completely blocked and partially reversed by inhibition of sclerostin but not by inhibition of TNF. Moreover, Scl-Ab completely arrested the progression of bone erosion in hTNFtg mice and in combination with TNF inhibition even led to significant regression of cortical bone erosions. Protective effects of Scl-Ab were also observed for the articular cartilage. CONCLUSIONS: These data suggest that sclerostin inhibition is a powerful tool to enhance bone repair in inflammatory arthritis.
Annals of the rheumatic diseases 05/2013; · 8.11 Impact Factor
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ABSTRACT: OBJECTIVES: Targeted therapies for systemic sclerosis (SSc) and other fibrotic diseases are not yet available. We evaluated the efficacy of heat shock protein 90 (Hsp90) inhibition as a novel approach to inhibition of aberrant transforming growth factor (TGF)-β signalling and for the treatment of fibrosis in preclinical models of SSc. METHODS: Expression of Hsp90 was quantified by quantitative PCR, western blot and immunohistochemistry. The effects of Hsp90 inhibition were analysed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, in tight-skin (Tsk-1) mice and in mice overexpressing a constitutively active TGF-β receptor I (TβRI). RESULTS: Expression of Hsp90β was increased in SSc skin and in murine models of SSc in a TGF-β-dependent manner. Inhibition of Hsp90 by 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) inhibited canonical TGF-β signalling and completely prevented the stimulatory effects of TGF-β on collagen synthesis and myofibroblast differentiation. Treatment with 17-DMAG decreased the activation of canonical TGF-β signalling in murine models of SSc and exerted potent antifibrotic effects in bleomycin-induced dermal fibrosis, in Tsk-1 mice and in mice overexpressing a constitutively active TβRI. Dermal thickness, number of myofibroblasts and hydroxyproline content were all significantly reduced on treatment with 17-DMAG. No toxic effects were observed with 17-DMAG at antifibrotic doses. CONCLUSIONS: Hsp90 is upregulated in SSc and is critical for TGF-β signalling. Pharmacological inhibition of Hsp90 effectively blocks the profibrotic effects of TGF-β in cultured fibroblasts and in different preclinical models of SSc. These results have translational implications, as several Hsp90 inhibitors are in clinical trials for other indications.
Annals of the rheumatic diseases 05/2013; · 8.11 Impact Factor
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ABSTRACT: OBJECTIVE: To test whether the tyrosine kinase Tyro3 affects arthritis. Tyro3, the ligand of growth arrest-specific protein 6 (GAS6) is a receptor tyrosine kinase involved in cell survival. Tyro3 and GAS6 are expressed in the arthritic synovium, and in vitro studies have shown their role in osteoclast differentiation. METHODS: Bone was assessed by micro CT and histomorphometry in Tyro3-deficient (Tyro3(-/-)) and wild-type mice. Arthritis was induced in both genotypes, and Gas6 level was measured by ELISA. Synovitis, synovial hyperplasia, bone erosion, osteoclast activation and osteoclast gene expression were assessed by histomorphometry and reverse transcriptase-PCR, respectively. In vitro osteoclast differentiation assays were performed in Tyro3(-/-) and wild-type mice. Furthermore, effects of Tyro3 and GAS6 on human synovial fibroblast proliferation and osteoclastogenesis were assessed in human cells. RESULTS: Tyro3(-/-) mice had significantly higher bone mass than wild-type littermates. Induction of arthritis increased GAS6 serum levels. Arthritic Tyro3(-/-) mice showed less synovial hyperplasia, osteoclast numbers and bone damage compared with controls. In vivo expression of osteoclast-associated receptor and receptor activator of nuclear factor-κB and in vitro osteoclastogenesis were impaired in Tyro3(-/-) mice. GAS6 also induced synovial fibroblast proliferation and osteoclast differentiation in human cells in Tyro3-dependent manner. CONCLUSIONS: These findings indicate that Tyro3 is a critical signal for synovial hyperplasia, osteoclast differentiation and bone erosion during arthritis. GAS6 and Tyro3 therefore constitute therapeutic targets to inhibit synovial hyperplasia and associated bone erosion.
Annals of the rheumatic diseases 04/2013; · 8.11 Impact Factor
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Barbara Herz,
Andreas Albrecht,
Matthias Englbrecht,
Götz H Welsch,
Michael Uder,
Nina Renner,
Philipp Schlechtweg,
Dominik Paul,
Lars Lauer,
Klaus Engelke,
Rolf Janka,
Jürgen Rech, Georg Schett,
Stephanie Finzel
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ABSTRACT: OBJECTIVES: To investigate the relation between anatomic changes of the synovium, the bone, the bone marrow and the cartilage to biochemical properties of the cartilage in patients with rheumatoid arthritis (RA). METHODS: 33 patients with RA received 3-T MRI scans of the metacarpophalangeal joints. Two independent methods, (A) the delayed gadolinium enhanced MRI of the cartilage (dGEMRIC, T2-mapping), which was used to assess the biochemical properties of the cartilage; (B) synovitis, osteitis and bone erosions were quantified according to the RA MRI scoring (RAMRIS) method and cartilage thickness (CT), interbone joint space (IBJS, distance between proximal and distal bone surface) and intercartilage joint space (ICJS, distance between proximal and distal cartilage surface) were measured. RESULTS: Biochemical changes of the cartilage, corresponding to low dGEMRIC and high T2 values, were more likely to be seen in joints with decreased IBJS and ICJS as well as decreased CT. For instance, dGEMRIC was directly correlated to the IBJS (p=0.001) and ICJS (p=0.001), whereas T2 mapping was inversely correlated to IBJS and ICJS (both p=0.017). Moreover, the degree of osteitis, and to some extent synovitis, was correlated to biochemical cartilage changes as measured by dGEMRIC (p=0.003) or the T2 mapping (p=0.013). By contrast, bone erosions did not correlate to the degree of biochemical cartilage changes. DISCUSSION: These data support the concept that synovitis and osteitis may be two main triggers for cartilage damage. Thus, the actual inflammatory state of a joint, but not so much the degree of bone erosion, appears to influence cartilage properties in RA.
Annals of the rheumatic diseases 04/2013; · 8.11 Impact Factor
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ABSTRACT: OBJECTIVES: The aim of this study was to assess the role of vascular adhesion molecule 1 (VCAM-1) in patients with hereditary haemochromatosis (HH) with or without arthropathy. METHODS: Sera from a large cross-sectional cohort of unselected HH patients (n=147) were obtained and compared to an age-matched and sex-matched control group. Serum levels of VCAM-1 were measured by ELISA and were correlated with clinical measures. RESULTS: VCAM-1 serum levels were elevated in HH patients as compared to matched controls (mean 913±456 vs 654±451 ng/ml, p<0.0001). Within the HH patient group, VCAM-1 levels were much higher in patients with arthropathy and joint replacement surgery. VCAM-1 levels correlated well with radiographic measures of HH arthropathy (r=0.36, p<0.0001). Multivariate regression analysis confirmed a highly significant association of VCAM-1 serum levels and the presence of HH arthropathy, independent from diabetes, body mass index and age. CONCLUSIONS: VCAM-1 serum levels emerge as a biomarker for haemochromatosis arthropathy.
Annals of the rheumatic diseases 04/2013; · 8.11 Impact Factor
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Christian Beyer,
Helena Reichert,
Hümeyra Akan,
Tatjana Mallano,
Amelie Schramm,
Clara Dees,
Katrin Palumbo-Zerr,
Neng Yu Lin,
Alfiya Distler,
Kolja Gelse,
John Varga,
Oliver Distler, Georg Schett,
Jörg H W Distler
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ABSTRACT: BACKGROUND AND OBJECTIVES: Fibrosis is a major socioeconomic burden, but effective antifibrotic therapies are not available in the clinical routine. There is growing evidence for a central role of Wnt signalling in fibrotic diseases such as systemic sclerosis, and we therefore evaluated the translational potential of pharmacological Wnt inhibition in experimental dermal fibrosis. METHODS: We examined the antifibrotic effects of PKF118-310 and ICG-001, two novel inhibitors of downstream canonical Wnt signalling, in the models of prevention and treatment of bleomycin-induced dermal fibrosis as well as in experimental dermal fibrosis induced by adenoviral overexpression of a constitutively active transforming growth factor (TGF)-β receptor I. RESULTS: PKF118-310 and ICG-001 were well tolerated throughout all experiments. Both therapeutic approaches showed antifibrotic effects in preventing and reversing bleomycin-induced dermal fibrosis as measured by skin thickness, hydroxyproline content and myofibroblast counts. PKF118-310 and ICG-001 were effective in inhibiting TGF-β receptor I-driven fibrosis as assessed by the same outcome measures. CONCLUSIONS: Blockade of canonical Wnt signalling by PKF118-310 and ICG-001 showed antifibrotic effects in different models of skin fibrosis. Both therapies were well tolerated. Although further experimental evidence for efficacy and tolerability is necessary, inhibition of canonical Wnt signalling is a promising treatment approach for fibrosis.
Annals of the rheumatic diseases 04/2013; · 8.11 Impact Factor
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ABSTRACT: OBJECTIVE: Apremilast, a specific inhibitor of phosphodiesterase 4, modulates proinflammatory and antiinflammatory cytokine production. A phase IIb randomized, controlled trial (RCT) evaluated the effect of apremilast on patient-reported outcomes (PRO) in psoriatic arthritis (PsA). METHODS: In this 12-week RCT, patients with active disease (duration > 6 mo, ≥ 3 swollen and ≥ 3 tender joints) received apremilast (20 mg BID or 40 mg QD) or placebo. PRO included pain and global assessment of disease activity [visual analog scale (VAS)], Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and Medical Outcomes Study Short-Form 36 Health Survey (SF-36) assessing health-related quality of life (HRQOL). Percentages of patients reporting improvements ≥ minimum clinically important differences (MCID) and correlations between SF-36 domains and pain VAS, HAQ-DI, and FACIT-F were determined. RESULTS: Among the 204 randomized patients (52.5% men; mean age 50.6 yrs), baseline SF-36 scores reflected large impairments in HRQOL. Apremilast 20 mg BID resulted in statistically significant and clinically meaningful improvements in physical and mental component summary scores and 7 and 6 SF-36 domains, respectively, compared with no change/deterioration in placebo group. Patients receiving apremilast 20 mg BID and 40 mg QD reported significant improvements ≥ MCID in global VAS scores and FACIT-F versus placebo, and significant improvements in pain VAS scores. Moderate-high, significant correlations were evident between SF-36 domains and other PRO. CONCLUSION: Apremilast resulted in statistically significant and clinically meaningful improvements in HRQOL, pain and global VAS, and FACIT-F scores.
The Journal of Rheumatology 04/2013; · 3.69 Impact Factor
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Carina Scholtysek,
Julia Katzenbeisser,
He Fu,
Stefan Uderhardt,
Natacha Ipseiz,
Cornelia Stoll,
Mario M Zaiss,
Michael Stock,
Laura Donhauser,
Christina Böhm,
Arnd Kleyer,
Andreas Hess,
Klaus Engelke,
Jean-Pierre David,
Farida Djouad,
Jan Peter Tuckermann,
Béatrice Desvergne, Georg Schett,
Gerhard Krönke
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ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) act as metabolic sensors and central regulators of fat and glucose homeostasis. Furthermore, PPARγ has been implicated as major catabolic regulator of bone mass in mice and humans. However, a potential involvement of other PPAR subtypes in the regulation of bone homeostasis has remained elusive. Here we report a previously unrecognized role of PPARβ/δ as a key regulator of bone turnover and the crosstalk between osteoblasts and osteoclasts. In contrast to activation of PPARγ, activation of PPARβ/δ amplified Wnt-dependent and β-catenin-dependent signaling and gene expression in osteoblasts, resulting in increased expression of osteoprotegerin (OPG) and attenuation of osteoblast-mediated osteoclastogenesis. Accordingly, PPARβ/δ-deficient mice had lower Wnt signaling activity, lower serum concentrations of OPG, higher numbers of osteoclasts and osteopenia. Pharmacological activation of PPARβ/δ in a mouse model of postmenopausal osteoporosis led to normalization of the altered ratio of tumor necrosis factor superfamily, member 11 (RANKL, also called TNFSF11) to OPG, a rebalancing of bone turnover and the restoration of normal bone density. Our findings identify PPARβ/δ as a promising target for an alternative approach in the treatment of osteoporosis and related diseases.
Nature medicine 03/2013; · 27.14 Impact Factor
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Arnd Kleyer,
Stephanie Finzel,
Jürgen Rech,
Bernhard Manger,
Manuel Krieter,
Francesca Faustini,
Elisabeth Araujo,
Axel J Hueber,
Ulrike Harre,
Klaus Engelke, Georg Schett
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ABSTRACT: OBJECTIVE: Anticitrullinated protein antibodies (ACPA) are a major risk factor for bone loss in rheumatoid arthritis (RA). We have recently shown that ACPA directly induce bone loss by stimulating osteoclast differentiation. As ACPA precede the clinical onset of RA by years, we hypothesised that ACPA positive healthy individuals may already show skeletal changes. METHODS: We performed a comparative micro-CT analysis of the bone microstructure in the metacarpophalangeal joints of ACPA positive and ACPA negative healthy individuals without clinical signs of arthritis. RESULTS: ACPA positive (n=15) and negative (n=15) healthy individuals were not different in age (48.2±4.1 vs 51.4±3.8 years, p=0.57) or gender (eight women and two men in both groups). Bone mineral density was significantly reduced in ACPA positive individuals (mean±SEM 280±11 mg/cm(3)) compared with controls (327±6). Bone loss was based on cortical bone changes, with significant (p=0.044) reduction in cortical thickness in the ACPA positive group (mean±SEM 0.22±0.03 mm) compared with controls (0.32±0.03 mm). Areas of cortical porosity were significantly (p=0.0005) more widespread in ACPA positive (mean±SEM 7.4±1.4%) than in ACPA negative individuals (1.0±0.3%). DISCUSSION: Structural bone damage starts before the clinical onset of arthritis in subjects with ACPA. These findings revise the concept that bone damage is an exclusive consequence of synovitis in patients with RA.
Annals of the rheumatic diseases 03/2013; · 8.11 Impact Factor
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Tobias Braun,
Johannes Lepper,
Gisela Ruiz Heiland,
Willy Hofstetter,
Mark Siegrist,
Patrick Lezuo,
Matthias Gaestel,
Monika Rumpler, Roman Thaler,
Klaus Klaushofer,
Jörg H W Distler, Georg Schett,
Jochen Zwerina
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Tobias Braun,
Johannes Lepper,
Gisela Ruiz Heiland,
Willy Hofstetter,
Mark Siegrist,
Patrick Lezuo,
Matthias Gaestel,
Monika Rumpler, Roman Thaler,
Klaus Klaushofer,
Jörg H W Distler, Georg Schett,
Jochen Zwerina
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ABSTRACT: OBJECTIVE.: The mechanisms involved in breaking immunological tolerance against nuclear autoantigens in systemic lupus erythematosus (SLE) are not fully understood. Our recent studies in non-autoimmune mice provided evidence of an important role of Toll-like receptor (TLR) 2 in anti-chromatin autoantibody induction by High Mobility Group Box protein 1 (HMGB1)-nucleosome complexes derived from apoptotic cells. Here we asked if TLR2 signaling is also required for the induction of autoantibodies and the development of SLE-like disease in murine pristane-induced lupus. METHODS.: Lupus-like disease in C57BL/6 and TLR2-/- mice was induced by pristane. The numbers of immune cells and serum cytokine concentrations were determined by flow cytometry. Renal disease was assessed by quantification of proteinuria, histological analyses and ELISPOT. RESULTS.: Pristane-injected TLR2-/- mice generated reduced numbers of splenic CD138+ / cytoplasmic κ/λ-L chain+ plasma cells and displayed diminished IgG responses against dsDNA, histones, nucleosomes, some extractable nuclear autoantigens (ENAs), and cardiolipin when compared with wild type controls. TLR2 deficiency prevented the pristane-induced systemic release of IL-6 and IL-10. Absence of TLR2 attenuated peritoneal recruitment of CD11c+ cells and formation of lipogranulomas. Importantly, pristane-treated TLR2-/- mice developed less severe renal disease compared to controls, reflected by milder proteinuria, reduced glomerular depositions of IgG and complement as well as decreased renal infiltration of autoantibody-secreting cells. CONCLUSION.: TLR2 is required for the production of prototypical lupus autoantibodies and the development of renal disease in pristane-induced murine lupus. Interference with TLR2 signaling may be a promising novel strategy for the treatment of SLE. © 2013 American College of Rheumatology.
Arthritis & Rheumatism 02/2013; · 7.87 Impact Factor
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Stefan Kiechl,
Jürgen Wittmann,
Andrea Giaccari,
Michael Knoflach,
Peter Willeit,
Aline Bozec,
Alexander R Moschen,
Giovanna Muscogiuri,
Gian Pio Sorice,
Trayana Kireva, [......],
Agnes Mayr,
Friedrich Oberhollenzer,
Florian Kronenberg,
Michael Orthofer,
Josef M Penninger,
James B Meigs,
Enzo Bonora,
Herbert Tilg,
Johann Willeit, Georg Schett
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ABSTRACT: Hepatic insulin resistance is a driving force in the pathogenesis of type 2 diabetes mellitus (T2DM) and is tightly coupled with excessive storage of fat and the ensuing inflammation within the liver. There is compelling evidence that activation of the transcription factor nuclear factor-κB (NF-κB) and downstream inflammatory signaling pathways systemically and in the liver are key events in the etiology of hepatic insulin resistance and β-cell dysfunction, although the molecular mechanisms involved are incompletely understood. We here test the hypothesis that receptor activator of NF-κB ligand (RANKL), a prototypic activator of NF-κB, contributes to this process using both an epidemiological and experimental approach. In the prospective population-based Bruneck Study, a high serum concentration of soluble RANKL emerged as a significant (P < 0.001) and independent risk predictor of T2DM manifestation. In close agreement, systemic or hepatic blockage of RANKL signaling in genetic and nutritional mouse models of T2DM resulted in a marked improvement of hepatic insulin sensitivity and amelioration or even normalization of plasma glucose concentrations and glucose tolerance. Overall, this study provides evidence for a role of RANKL signaling in the pathogenesis of T2DM. If so, translation to the clinic may be feasible given current pharmacological strategies to lower RANKL activity to treat osteoporosis.
Nature medicine 02/2013; · 27.14 Impact Factor
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ABSTRACT: Significance: In the cells' nuclei high mobility group box protein 1 (HMGB1) is a nonhistone-chromatin-binding protein involved in the regulation of transcription. Extracellularly, HMGB1 acts as a danger molecule with properties of a pro-inflammatory cytokine. It can be actively secreted from myeloid cells or passively leak from any type of injured, necrotic cell. Increased serum levels of active HMGB1 are often found in pathogenic inflammatory conditions and correlate with worse prognoses in cancer, sepsis and autoimmunity. By damaging cells, superoxide and peroxynitrite promote leakage of HMGB1. Recent advances: The activity of HMGB1 strongly depends on its redox state: Inflammatory active HMGB1 requires an intramolecular disulfide bond (Cys23 and Cys45) and a reduced Cys106. Oxidation of the latter blocks its stimulatory activity and promotes immune tolerance. Critical issues: Reactive oxygen and nitrogen species create an oxidative environment and can be detoxified by superoxide dismutase (SOD), catalase and peroxidases. Modifications of the oxidative environment influence HMGB1 activity. Future directions: In this review we hypothesize that manipulations of an oxidative environment by SOD mimics or by hydrogen sulfide are prone to decrease tissue damage. Both, the concomitant decreased HMGB1 release and its redox chemical modifications ameliorate inflammation and tissue damage.
Antioxidants & Redox Signaling 02/2013; · 8.20 Impact Factor
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ABSTRACT: OBJECTIVE: To evaluate the impact of the interaction of physical function and emotional well-being on disease-related parameters and coping with rheumatoid arthritis. METHODS: A cross-sectional survey among 177 RA patients included demographic and disease-related variables as well as the following patient-reported outcome measures: Health Assessment Questionnaire-Disability Index (HAQ-DI) (physical function), Mental Component Summary Scale of the SF-36 (MCSS) for emotional well-being, Rheumatoid Arthritis Disease Activity Index (RADAI), and Coping with Rheumatoid Arthritis Questionnaire (C-RAQ). Based on HAQ-DI and MCSS, six categories representing various levels of physical and emotional impairment were formed. Multivariate analysis of variance and a subsequent discriminant analysis were used to evaluate whether demographic and disease-related variables and coping strategies differed between these categories. RESULTS: Patients with moderate to high impairment of physical function and emotional well-being reported significantly higher disease activity and a more frequent use of distancing and active problem solving coping strategies than patients with low-level impairment (p<0.001-0.043). Furthermore, these patients reported experiencing significantly higher levels of helplessness (p<0.001-0.032). Results from the discriminant analysis highlighted a combination of disease activity and helplessness to differentiate best between patients with either low or high impairment of physical function and emotional well-being (p<0.001). CONCLUSION: Aside from perceived disease activity, helplessness, and distancing as well as active problem solving allowed for a good discrimination between the different levels of impairment of physical function and emotional well-being. Encouraging and educating patients on how to cognitively reframe their current situation might play a key role in reducing the level of helplessness resulting from impairments of physical function and emotional well-being.
Seminars in arthritis and rheumatism 01/2013; · 4.72 Impact Factor
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ABSTRACT: Objective. Haemochromatosis arthropathy is a secondary OA and the most frequent and earliest clinical presentation of hereditary haemochromatosis (HH). The aim of this study was to perform a direct clinical, functional and radiographic comparison with idiopathic hand OA (HOA) to unravel important differences between these clinical entities.Methods. In total, 299 patients (141 with HH arthropathy of the hands and 158 patients with idiopathic HOA) were recruited. Structured clinical assessment including hand function tests, as well as hand radiographs with scoring according to Kellgren-Lawrence, were carried out in all patients.Results. HH arthropathy and HOA differed significantly: patients with HH arthropathy were younger and predominantly male as compared with HOA. In males but not females, HH arthropathy led to an earlier start of symptoms than in HOA. Patients with HOA had more tender joints and worse hand function than patients with HH arthropathy, although subjective measures of joint pain and function were similar. MCP and wrist joint involvement was more frequent and severe in HH arthropathy, while HOA patients more frequently had degenerative changes in the first CMC as well as PIP and DIP joints.Conclusion. HH arthropathy and idiopathic HOA differ significantly in terms of epidemiology, localization, severity of symptoms and radiographic changes.
Rheumatology (Oxford, England) 01/2013; · 4.24 Impact Factor
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Nature Reviews Rheumatology 01/2013; · 8.39 Impact Factor
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Christian Beyer,
Alla Skapenko,
Alfiya Distler,
Clara Dees,
Helena Reichert,
Louis Munoz,
Jan Leipe,
Hendrik Schulze-Koops,
Oliver Distler, Georg Schett,
Jörg H W Distler
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ABSTRACT: OBJECTIVE: To assess the antifibrotic effects of pregnane X receptors (PXRs) in experimental dermal fibrosis. METHODS: The antifibrotic effects of PXR activation by 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN) were studied in the bleomycin model for prevention of dermal fibrosis and the modified bleomycin model for the treatment of established bleomycin-induced dermal fibrosis. Activation of canonical transforming growth factor (TGF)β signalling was analysed by immunofluorescence staining for phosphorylated smads. The antifibrotic effects of PXR activation were further studied in murine fibroblasts and murine T cells under Th2 conditions. In the T cell experiments, synthesis of the profibrotic cytokines, interleukin (IL)-4 and IL-13, was assessed by quantitative PCR, and IL-13 levels in the murine skin were determined by multiplex bead array technology. RESULTS: Activation of PXR effectively inhibited the development of bleomycin-induced dermal fibrosis and induced the regression of established dermal fibrosis as assessed by skin thickening, hydroxyproline content and myofibroblasts. Reduced levels of phosphorylated smad2 and smad3 suggested that the antifibrotic effects of PXRs were mediated by inhibition of canonical TGFβ signalling. While PXR activation appeared to have no direct effects on fibroblasts, it potently inhibited the release of the profibrotic cytokine, IL-13, from Th2 cells. Consistent with these findings, IL-13 levels were reduced in bleomycin-challenged murine skin upon PXR activation. CONCLUSIONS: Our findings demonstrate a novel antifibrotic role for PXRs in inflammatory dermal fibrosis. The antifibrotic effects of PXRs appear to be indirect: PXR activation reduces the release of the Th2 cytokine, IL-13, from T cells resulting in decreased canonical TGFβ signalling.
Annals of the rheumatic diseases 01/2013; · 8.11 Impact Factor
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Arthritis & Rheumatism 01/2013; 65(1):12-20. · 7.87 Impact Factor
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Ralf Müller,
Christoph Daniel,
Christian Hugo,
Kerstin Amann,
Dirk Mielenz,
Karlhans Endlich,
Tobias Braun,
Betty van der Veen,
Peter Heeringa, Georg Schett,
Jochen Zwerina
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ABSTRACT: p38 mitogen-activated protein kinase (MAPK) is thought to play a central role in acute and chronic inflammatory responses. Whether p38MAPK plays a pathogenic role in crescentic GN (GN) and which of its four isoforms is preferentially involved in kidney inflammation is not definitely known. We thus examined expression and activation of p38MAPK isoforms during anti-glomerular basement membrane (GBM) nephritis. Therefore, p38α conditional knockout mice (MxCre-p38α(Δ/Δ)) were used to examine the role of p38α in anti-GBM induced nephritis. Both wild type and MxCre-p38α(Δ/Δ) mice developed acute renal failure over time. Histological examinations revealed a reduced monocyte influx and less tubular damage in MxCre-p38α(Δ/Δ) mice, whereas glomerular crescent formation and renal fibrosis was similar. Likewise, the levels of pro- and anti-inflammatory cytokines such as TNF, IL-1 and IL-10 were similar, but IL-8 was even up-regulated in MxCre-p38α(Δ/Δ) mice. In contrast, we could detect strong down-regulation of chemotactic cytokines such as CCL-2, -5 and -7, in the kidneys of MxCre-p38α(Δ/Δ) mice. In conclusion, p38α is the primary p38MAPK isoform expressed in anti-GBM nephritis and selectively affects inflammatory cell influx and tubular damage. Full protection from nephritis is however not achieved as renal failure and structural damage still occurs.
PLoS ONE 01/2013; 8(2):e56316. · 4.09 Impact Factor
