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This study aims to quantitatively describe anatomic changes in systemic sclerosis (SSc)\u2013skin compared with controls and investigate the underlying mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Skin morphology was histologically assessed in 23 patients with SSc, 18 controls, and 15 patients with hypertrophic scars. Spatial WNT\/\u03b2\u2010catenin\u2010activation was analyzed by RNAscope and immunofluorescence staining. Enrichment of reticular marker genes in predefined fibroblast subpopulations was done using Gene Ontology (GO) enrichment and gene set enrichment analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SSc skin showed a decrease in number (<jats:italic>P<\/jats:italic> &lt; 0.0001\/<jats:italic>P<\/jats:italic> = 0.0004), area (<jats:italic>P<\/jats:italic> &lt; 0.0001), and height (<jats:italic>P<\/jats:italic> &lt; 0.0001) of papillae compared with controls and hypertrophic scars, respectively. The expression of papillary\/reticular marker genes shifted toward a reticular expression profile in SSc. On the level of previously defined fibroblast populations, the increase of reticular marker genes was particularly pronounced in the PI16+ and SFRP4+ populations (<jats:italic>P<\/jats:italic> &lt; 0.0001, respectively). Mechanistically, the expression of the WNT\/\u03b2\u2010catenin target <jats:italic>AXIN2<\/jats:italic> and the number of fibroblasts with nuclear \u03b2\u2010catenin\u2010staining\u2010pattern increased in the papillary compared with the reticular dermis in healthy skin. This polarization was lost in SSc with a two\u2010fold increase in \u03b2\u2010catenin\u2010positive fibroblasts and <jats:italic>AXIN2<\/jats:italic>\u2010expressing fibroblasts throughout the dermis (<jats:italic>P<\/jats:italic> = 0.0095). Enrichment of genes related to WNT\/\u03b2\u2010catenin\u2010regulation was found in the PI16+ population that also relocates from the reticular to the papillary dermis in SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We demonstrate an association of the \u201creticularized\u201d skin phenotype in SSc with a profound loss of physiologic spatial WNT\/\u03b2\u2010catenin\u2010activation. Rescuing the spatial WNT\/\u03b2\u2010catenin\u2010activation might help restore the physiologic skin organization in future therapeutic approaches of fibrosing disorders.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.43094","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:20:31Z","timestamp":1735172431000},"page":"740-749","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Disturbed Spatial <scp>WNT<\/scp> Activation\u2014A Potential Driver of the Reticularized Skin Phenotype in Systemic Sclerosis"],"prefix":"10.1002","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6302-0867","authenticated-orcid":false,"given":"Sara Chenguiti","family":"Fakhouri","sequence":"first","affiliation":[{"name":"Department of Internal Medicine 3 \u2010 Rheumatology and Clinical Immunology, Friedrich\u2010Alexander\u2010University (FAU) Erlangen\u2010N\u00fcrnberg and Uniklinikum Erlangen, Erlangen, Germany, and Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen\u2010N\u00fcrnberg and Uniklinikum Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8724-2835","authenticated-orcid":false,"given":"Honglin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Xiangya Hospital Central South University  Changsha Hunan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8934-9361","authenticated-orcid":false,"given":"Yi\u2010Nan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University, D\u00fcsseldorf, Germany, and Hiller Research Center University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Ronicke","sequence":"additional","affiliation":[{"name":"Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen\u2010N\u00fcrnberg and Uniklinikum Erlangen, Erlangen, Germany, and Department of Dermatology Friedrich\u2010Alexander\u2010University (FAU) Erlangen\u2010N\u00fcrnberg and Uniklinikum Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleix Rius","family":"Rigau","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 3 \u2010 Rheumatology and Clinical Immunology, Friedrich\u2010Alexander\u2010University (FAU) Erlangen\u2010N\u00fcrnberg and Uniklinikum Erlangen, Erlangen, Germany, and Deutsches Zentrum Immuntherapie (DZI) FAU Erlangen\u2010N\u00fcrnberg and Uniklinikum Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Dees","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 3 \u2010 Rheumatology and Clinical Immunology, Friedrich\u2010Alexander\u2010University (FAU) Erlangen\u2010N\u00fcrnberg and Uniklinikum Erlangen, Erlangen, Germany, and Deutsches Zentrum Immuntherapie (DZI), FAU Erlangen\u2010N\u00fcrnberg and Uniklinikum Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Konstantinidis","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 3 \u2010 Rheumatology and Clinical Immunology, Friedrich\u2010Alexander\u2010University (FAU) Erlangen\u2010N\u00fcrnberg and Uniklinikum Erlangen, Erlangen, Germany, and Deutsches Zentrum Immuntherapie (DZI) FAU Erlangen\u2010N\u00fcrnberg and Uniklinikum Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Schmid","sequence":"additional","affiliation":[{"name":"Department of Plastic and Hand Surgery, Laboratory for Tissue Engineering and Regenerative Medicine, University Hospital Erlangen Friedrich Alexander University Erlangen\u2010N\u00fcrnberg FAU  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1248-3145","authenticated-orcid":false,"given":"Alexandru\u2010Emil","family":"Matei","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University, D\u00fcsseldorf, Germany, and Hiller Research Center, University Hospital D\u00fcsseldorf, Medical Faculty of Heinrich Heine University, D\u00fcsseldorf, Germany; 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