Critical Role for Transglutaminase 2 in Scleroderma Skin Fibrosis and in the Development of Dermal Sclerosis in a Mouse Model of Scleroderma

IF 10.9 1区医学 Q1 RHEUMATOLOGY Arthritis & Rheumatology Pub Date : 2025-01-12 DOI:10.1002/art.43104

Angela Y. Y. Tam, Korsa Khan, Shiwen Xu, Marianne Bergin, Linghong Huang, Erik Arroyo Colon, Danyi Cheng, Elisabetta A. M. Verderio, Voon Ong, Christopher P. Denton, John Atkinson, Tim S. Johnson, David J. Abraham

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Abstract

Objective

Scleroderma is a life-threatening autoimmune disease characterized by inflammation, tissue remodeling, and fibrosis. This study aimed to investigate the expression and function of transglutaminase 2 (TGM2) in scleroderma skin and experimentally induced dermal fibrosis to determine its potential role and therapeutic implications.

Methods

We performed immunohistochemistry on skin sections to assess TGM2 expression and localization, and protein biochemistry of both systemic sclerosis–derived and healthy control dermal fibroblasts to assess TGM2 expression, function, and extracellular matrix deposition in the presence of TGM2 inhibiting and transforming growth factor (TGF)-β neutralizing antibodies and a small-molecule inhibitor of the TGF-βRI kinase. Mice with a complete deficiency of TGM2 (Tgm2-/-) were investigated in the bleomycin-induced model of skin fibrosis.

Results

TGM2 was found to be widely expressed in both control and scleroderma skin samples, as well as in cultured fibroblasts. Scleroderma fibroblasts exhibited elevated TGM2 expression, which correlated with increased expression of fibrosis markers (Col-1, αSMA, and CCN2). Inhibition of TGM2 using an inhibiting antibody reduced the expression of key markers of fibrosis. The effects of TGM2 inhibition were similar to those observed with TGF-β neutralization, suggesting a potential crosstalk between TGM2 and TGF-β signaling. Moreover, TGM2 knockout mice showed significantly reduced dermal fibrosis compared with wild type mice. In vitro experiments with TGM2-deleted fibroblasts demonstrated impaired cell migration and collagen matrix contraction, which could be partially restored by exogenous TGF-β.

Conclusion

TGM2 can regulate several key profibrotic activities of TGF-β suggesting that attenuating TGM2 function may be of benefit in severe forms of connective tissue disease with skin fibrosis.

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在硬皮病小鼠模型中，转谷氨酰胺酶2在硬皮病皮肤纤维化和真皮硬化症发展中的关键作用

硬皮病是一种以炎症、组织重塑和纤维化为特征的危及生命的自身免疫性疾病。本研究旨在探讨转谷氨酰胺酶2 （TGM2）在硬皮病皮肤和实验性皮肤纤维化中的表达和功能，以确定其潜在的作用和治疗意义。

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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.