Tam, Angela YY;
Khan, Korsa;
Xu, Shiwen;
Bergin, Marianne;
Huang, Linghong;
Arroyo Colon, Erik;
Cheng, Danyi;
... Abraham, David J; + view all
(2025)
Critical role for Transglutaminase 2 in scleroderma skin fibrosis and in the development of dermal sclerosis in a mouse model of scleroderma.
Arthritis & Rheumatology
10.1002/art.43104.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Critical role for Transglutaminase 2 in scleroderma skin fibrosis and in the development of dermal sclerosis in a mouse model of scleroderma |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/art.43104 |
| Publisher version: | https://doi.org/10.1002/art.43104 |
| Language: | English |
| Additional information: | © 2025 UCB and The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10203485 |
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