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However, the consequences of their concomitant up\u2010regulation are unknown. Here, we tested the hypothesis that mutual amplification of both pathways might drive persistent fibroblast activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cultured fibroblasts and skin sections of patients with diffuse SSc and healthy volunteers were analyzed. cJUN\/AP\u20101 signaling and hedgehog\/GLI2 signaling were inhibited using knockdown and pharmacologic approaches. Hedgehog signaling was activated in mice by fibroblast\u2010specific overexpression of constitutively active Smoothened.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>cJUN and GLI2 are concomitantly up\u2010regulated and colocalize in fibroblasts of patients with SSc compared to healthy controls. Activation of hedgehog\/GLI2 signaling induces the expression of cJUN in vitro and in vivo, whereas inactivation of GLI2 inhibits cJUN expression. Likewise, inactivation of cJUN impairs the expression of GLI2. This mutual regulation occurs at the level of transcription with binding of cJUN and GLI2 to specific binding motifs. Interference with this mutual amplification of cJUN signaling and GLI2 signaling inhibits fibroblast activation and collagen release: Inhibition of cJUN\/AP\u20101 signaling ameliorates hedgehog\u2010induced fibroblast activation and skin fibrosis in Smo<jats:sup>ACT<\/jats:sup> mice with a reduction of skin thickness of 103% (<jats:italic>P<\/jats:italic> = 0.0043) in the treatment group compared to the fibrotic control group. Moreover, combined pharmacologic inhibition of cJUN\/AP\u20101 and hedgehog\/GLI2 exerts additive antifibrotic effects in a model of TGF\u03b2\u2010driven experimental fibrosis (TBR<jats:sup>ACT<\/jats:sup> mice).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The transcription factors cJUN and GLI2 reinforce each other's activity to promote fibroblast activation in SSc. Interruption of this crosstalk by combined inhibition of both pathways exerts additive antifibrotic effects at well\u2010tolerated doses.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42979","type":"journal-article","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T22:49:17Z","timestamp":1724712557000},"page":"92-98","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Mutual Amplification of <scp>GLI2<\/scp>\/Hedgehog and Transcription Factor <scp>JUN<\/scp>\/<scp>AP<\/scp>\u20101 Signaling in Fibroblasts in Systemic Sclerosis: Potential Implications for Combined Therapies"],"prefix":"10.1002","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5257-9171","authenticated-orcid":false,"given":"Christina","family":"Bergmann","sequence":"first","affiliation":[{"name":"Deutsches Zentrum f\u00fcr Immuntherapie, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg and Uniklinikum 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