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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\n      \u003Ch2\u003ESummary\u003C\/h2\u003E\n      \u003Cp id=\u0022p-1\u0022\u003EThis article discusses a study that explored the potential role of Janus kinase 2 (JAK2) as a molecular target for the treatment of fibrotic disease. In this study, inhibition of JAK2 reduced the basal synthesis of collagen selectively in systemic sclerosis fibroblasts but not in control fibroblasts.\u003C\/p\u003E\n   \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Erheumatology clinical trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Erheumatological autoimmune disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n      \u003Cp id=\u0022p-2\u0022\u003EA study that explored the potential role of Janus kinase 2 (JAK2) as a molecular target for the treatment of fibrotic disease was presented by Clara Dees, PhD, University of Erlangen-Nuremberg, Erlangen, Germany. In this study, inhibition of JAK2 reduced the basal synthesis of collagen selectively in systemic sclerosis (SSc) fibroblasts but not in control fibroblasts. The profibrotic effects of transforming growth factor beta (TGF\u03b2) were nullified with inhibition of JAK2. Inhibition of JAK2 also prevented fibrosis in inflammatory and noninflammatory fibrosis models.\u003C\/p\u003E\n      \u003Cp id=\u0022p-3\u0022\u003ESSc is characterized by an uncontrolled activation of fibroblasts, resulting in the release of excessive amounts of extracellular matrix components, leading to thickening and tightening of the skin. This study evaluated the role of JAK2 in the pathogenesis of SSc and analyzed the potential role of JAK2 inhibition as a novel antifibrotic.\u003C\/p\u003E\n      \u003Cp id=\u0022p-4\u0022\u003EActivation of JAK2 was determined by immunohistochemistry for phospho-JAK2 and phosphosignal transducers and activators of transcription 3 (STAT3; a major STAT protein that is activated by JAK2). Dermal fibroblasts were stimulated with TGF\u03b2 (a key factor in fibroblast activation in SSc) and incubated with the specific JAK2 inhibitor TG101209 at different concentrations. Fibroblast activation was determined by staining for \u03b1-smooth muscle actin (\u03b1SMA) and stress fibers. Bleomycin-induced dermal fibrosis and tight-skin 1 (Tsk-1) mice were used to evaluate the antifibrotic potential of a specific JAK2 inhibition \u003Cem\u003Ein vivo.\u003C\/em\u003E\n         \u003C\/p\u003E\n      \u003Cp id=\u0022p-5\u0022\u003EIncreased activation of JAK2 with prominent accumulation of phospho-JAK2, particularly in fibroblasts, was observed in the skin of SSc mice. JAK2 signaling persisted in cultured SSc fibroblasts, and stimulation of healthy fibroblasts with TGF\u03b2 increased the levels of phospho-JAK2, similar to those seen in SSc fibroblasts. Inhibition of JAK2 with TG101209 prevented the activation of SSc fibroblasts in the presence of TGF\u03b2 stimulation and decreased \u03b1SMA almost back to baseline levels. TGF\u03b2-induced collagen synthesis (collagen type 1, alpha 1 [col1A1] mRNA, and collagen protein) was also reduced.\u003C\/p\u003E\n      \u003Cp id=\u0022p-6\u0022\u003EFurthermore, inhibition of JAK2 by the selective JAK2 inhibitor TG101209 abrogated the activated phenotype of SSc fibroblasts by decreasing the formation of stress fibers, the expression of \u03b1SMA, and the basal mRNA and protein levels of collagen. These inhibitory effects in the absence of exogenous stimulation were only observed in SSc fibroblasts, not in resting dermal fibroblasts from healthy individuals.\u003C\/p\u003E\n      \u003Cp id=\u0022p-7\u0022\u003EInhibition of JAK2 consistently exerted potent antifibrotic effects in experimental fibrosis. In the model of bleomycin-induced fibrosis, treatment with TG101209 decreased dermal thickening by 95%+5% (p=0.007), collagen content by 76%+7% (p\u0026lt;0.001), and myofibroblast counts completely back to baseline levels (p=0.001). Potent antifibrotic effects were also observed in the Tsk-1 model. Application of TG101209 reduced hypodermal thickening, collagen content, and myofibroblast counts (p=0.01). These results suggest that JAK2 might be a promising molecular target for the treatment of SSc and other fibrotic diseases.\u003C\/p\u003E\n   \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2011 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/11\/13\/16.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmw81\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}