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Researchers have identified a shift toward reticular gene expression in systemic sclerosis (SSc) skin, with disruptions in WNT/β-catenin signaling playing a key role in these changes.
Authors for the study, published in Arthritis and Rheumatology, analyzed skin morphology and molecular mechanisms in 23 SSc patients (18 in a control group, and 15 with hypertrophic scars). SSc skin exhibited decreased papillae number, area, and height compared to controls and hypertrophic scars (all P < 0.0001), along with a loss of the typical papillary/reticular marker gene profile. The expression of reticular marker genes was elevated in fibroblast populations expressing PI16+ and SFRP4+ (P < 0.0001).
Mechanistically, the spatial activation of WNT/β-catenin signaling, characterized by nuclear β-catenin and AXIN2 expression, was disrupted in those SSc skin. In healthy dermis, the papillary zone showed higher WNT/β-catenin activity; this polarization was lost in SSc skin, with a twofold increase in β-catenin-positive fibroblasts throughout the dermis (P = 0.0095). Gene enrichment analysis indicated WNT/β-catenin regulation was particularly active in the PI16+-population.
"We demonstrate an association of the 'reticularized' skin phenotype in SSc with a profound loss of physiological spatial WNT/β-catenin-activation," the authors wrote. "Rescuing the spatial WNT/β-catenin-activation might help restore the physiological skin organization in future therapeutic approaches of fibrosing disorders."
Source: Fakhouri SC, et al. Arthritis and Rheumatology. 2025. Doi:10.1002/art.43094