Disturbed Spatial WNT Activation—A Potential Driver of the Reticularized Skin Phenotype in Systemic Sclerosis

IF 10.9 1区医学 Q1 RHEUMATOLOGY Arthritis & Rheumatology Pub Date : 2024-12-25 DOI:10.1002/art.43094

Sara Chenguiti Fakhouri, Honglin Zhu, Yi-Nan Li, Moritz Ronicke, Aleix Rius Rigau, Clara Dees, Laura Konstantinidis, Ralf Schmid, Alexandru-Emil Matei, Markus Eckstein, Carol Geppert, Ingo Ludolph, Alexander Kreuter, Michael Sticherling, Carola Berking, Raymund E. Horch, Georg Schett, Jörg H. W. Distler, Christina Bergmann

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Abstract

Objective

Little is known on the mechanisms necessary to maintain the physiologic adult human skin integrity. This study aims to quantitatively describe anatomic changes in systemic sclerosis (SSc)–skin compared with controls and investigate the underlying mechanisms.

Methods

Skin morphology was histologically assessed in 23 patients with SSc, 18 controls, and 15 patients with hypertrophic scars. Spatial WNT/β-catenin-activation 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.

Results

SSc skin showed a decrease in number (P < 0.0001/P = 0.0004), area (P < 0.0001), and height (P < 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 (P < 0.0001, respectively). Mechanistically, the expression of the WNT/β-catenin target AXIN2 and the number of fibroblasts with nuclear β-catenin-staining-pattern increased in the papillary compared with the reticular dermis in healthy skin. This polarization was lost in SSc with a two-fold increase in β-catenin-positive fibroblasts and AXIN2-expressing fibroblasts throughout the dermis (P = 0.0095). Enrichment of genes related to WNT/β-catenin-regulation was found in the PI16+ population that also relocates from the reticular to the papillary dermis in SSc.

Conclusion

We demonstrate an association of the “reticularized” skin phenotype in SSc with a profound loss of physiologic spatial WNT/β-catenin-activation. Rescuing the spatial WNT/β-catenin-activation might help restore the physiologic skin organization in future therapeutic approaches of fibrosing disorders.

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WNT空间激活紊乱——系统性硬化症（SSc）网状皮肤表型的潜在驱动因素

对于维持成人皮肤完整的生理机制，我们所知甚少。本研究旨在定量描述与对照组相比，系统性硬化症（SSc）皮肤的解剖学变化，并探讨其潜在机制。

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来源期刊

Arthritis & Rheumatology RHEUMATOLOGY-

CiteScore

20.90

自引率

3.00%

发文量

371

期刊介绍： Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.