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- Title
Syndecan-2 regulates PAD2 to exert antifibrotic effects on RA-ILD fibroblasts.
- Authors
Tsoyi, Konstantin; Esposito, Anthony J.; Sun, Bo; Bowen, Ryan G.; Xiong, Kevin; Poli, Fernando; Cardenas, Rafael; Chu, Sarah G.; Liang, Xiaoliang; Ryter, Stefan W.; Beeton, Christine; Doyle, Tracy J.; Robertson, Matthew J.; Celada, Lindsay J.; Romero, Freddy; El-Chemaly, Souheil Y.; Perrella, Mark A.; Ho, I.-Cheng; Rosas, Ivan O.
- Abstract
Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however, the role of protein citrullination in RA-ILD remains unclear. Here, we demonstrate that the expression of peptidylarginine deiminase 2 (PAD2), an enzyme that catalyzes protein citrullination, is increased in lung homogenates from subjects with RA-ILD and their lung fibroblasts. Chemical inhibition or genetic knockdown of PAD2 in RA-ILD fibroblasts attenuated their activation, marked by decreased myofibroblast differentiation, gel contraction, and extracellular matrix gene expression. Treatment of RA-ILD fibroblasts with the proteoglycan syndecan-2 (SDC2) yielded similar antifibrotic effects through regulation of PAD2 expression, phosphoinositide 3-kinase/Akt signaling, and Sp1 activation in a CD148-dependent manner. Furthermore, SDC2-transgenic mice exposed to bleomycin-induced lung injury in an inflammatory arthritis model expressed lower levels of PAD2 and were protected from the development of pulmonary fibrosis. Together, our results support a SDC2-sensitive profibrotic role for PAD2 in RA-ILD fibroblasts and identify PAD2 as a promising therapeutic target of RA-ILD.
- Subjects
SYNDECANS; FIBROBLASTS; INTERSTITIAL lung diseases; LUNGS; MYOFIBROBLASTS; PULMONARY fibrosis; EXTRACELLULAR matrix
- Publication
Scientific Reports, 2022, Vol 12, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-022-06678-7