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The aim of this study was to test the hypothesis that the receptor tyrosine kinase EphB2 mediates dermal fibrosis in systemic sclerosis (SSc).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We assessed normal and SSc human skin biopsies for EphB2 expression. The in vivo role of EphB2 in skin fibrosis was investigated by subjecting\n                      <jats:italic>EphB2<\/jats:italic>\n                      \u2010knockout mice to both bleomycin\u2010induced and tight skin (\n                      <jats:italic>Tsk1<\/jats:italic>\n                      \/+) genetic mouse models of skin fibrosis. EphB2 kinase\u2010dead and overactive point mutant mice were used to evaluate the role of EphB2 forward signaling in bleomycin\u2010induced dermal fibrosis. In vitro studies were performed on dermal fibroblasts from patients with SSc and healthy controls, which was followed by in vivo analysis of fibroblast\u2010specific\n                      <jats:italic>Ephb2<\/jats:italic>\n                      \u2010deficient mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Expression of EphB2 is up\u2010regulated in SSc skin tissue and explanted SSc dermal fibroblasts compared with healthy controls. EphB2 expression is elevated in two animal models of dermal fibrosis. In mice, EphB2 drives dermal fibrosis in both the bleomycin and the Tsk1\/+ models of skin fibrosis. EphB2 forward signaling is a critical mediator of dermal fibrosis. Transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2) cytokines up\u2010regulate EphB2 in dermal fibroblasts via noncanonical TGF\u2010\u03b2\/mother against decapentaplegic signaling, and silencing\n                      <jats:italic>EPHB2<\/jats:italic>\n                      in human dermal fibroblasts is sufficient to dampen TGF\u2010\u03b2\u2013induced fibroblast\u2010to\u2010myofibroblast differentiation. Moreover, mice with fibroblast\u2010specific deletion of\n                      <jats:italic>EphB2<\/jats:italic>\n                      showed impaired fibroblast\u2010to\u2010myofibroblast differentiation and reduced skin fibrosis upon bleomycin challenge.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our data implicate TGF\u2010\u03b2 regulation of EphB2 overexpression and kinase\u2010mediated forward signaling in the development of dermal fibrosis in SSc. EphB2 thus represents a potential new therapeutic target for SSc.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.42858","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T22:24:25Z","timestamp":1712615065000},"page":"1303-1316","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["EphB2 Receptor Promotes Dermal Fibrosis in Systemic Sclerosis"],"prefix":"10.1002","volume":"76","author":[{"given":"Erika S. 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