Critical role for Transglutaminase 2 in scleroderma skin fibrosis and in the development of dermal sclerosis in a mouse model of scleroderma

Tam, AYY, Khan, K, Xu, S, Bergin, M, Huang, L, Arroyo Colon, E, Cheng, D, Verderio, E ORCID: https://orcid.org/0000-0001-9153-8997, Ong, V, Denton, CP, Atkinson, J, Johnson, TS and Abraham, DJ, 2025. Critical role for Transglutaminase 2 in scleroderma skin fibrosis and in the development of dermal sclerosis in a mouse model of scleroderma. Arthritis and Rheumatology. ISSN 2326-5191

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Abstract

Objective

Scleroderma is a life-threatening autoimmune disease characterized by inflammation, tissue remodelling, 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 localisation, and protein biochemistry of both SSc-derived and healthy control dermal fibroblasts to assess TGM2 expression, function and ECM deposition in the presence of a TGM2 and TGFβ neutralizing antibodies and a small molecule inhibitor of the TGFβRI 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 (collagen type 1, αSMA and CCN2). Inhibition of TGM2 using a neutralizing antibody reduced the expression of key markers of fibrosis. The effects of TGM2 inhibition were similar to those observed with TGFβ neutralization, suggesting a potential cross-talk between TGM2 and TGFβ signalling. Moreover, TGM2 knock-out mice showed significantly reduced dermal fibrosis compared to 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 TGFβ.

Conclusion

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

Item Type:	Journal article
Publication Title:	Arthritis and Rheumatology
Creators:	Tam, A.Y.Y., Khan, K., Xu, S., Bergin, M., Huang, L., Arroyo Colon, E., Cheng, D., Verderio, E., Ong, V., Denton, C.P., Atkinson, J., Johnson, T.S. and Abraham, D.J.
Publisher:	Wiley
Date:	12 January 2025
ISSN:	2326-5191
Identifiers:	Number Type 10.1002/art.43104 DOI 2358173 Other
Rights:	This is the peer reviewed version of the following article: [Tam, A.Y.Y., Khan, K., Xu, S., Bergin, M., Huang, L., Arroyo Colon, E., Cheng, D., Verderio, E., Ong, V., Denton, C.P., Atkinson, J., Johnson, T.S. and Abraham, D.J. (2025), Critical role for Transglutaminase 2 in scleroderma skin fibrosis and in the development of dermal sclerosis in a mouse model of scleroderma. Arthritis Rheumatol. Accepted Author Manuscript] which has been published in final form at https://doi.org/10.1002/art.43104. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.
Divisions:	Schools > School of Science and Technology
Record created by:	Melissa Cornwell
Date Added:	14 Feb 2025 10:42
Last Modified:	14 Feb 2025 10:42
URI:	https://irep.ntu.ac.uk/id/eprint/53040

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