Syndecan-2 regulates PAD2 to exert antifibrotic effects on RA-ILD fibroblasts

• Published in: Scientific reports Vol. 12; no. 1; pp. 2847 - 11
• Main 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-02-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 692/420; 692/699/1670/498; 692/699/1785; AKT protein; Animals; Anti-Citrullinated Protein Antibodies - genetics; Arthritis; Arthritis, Rheumatoid - complications; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - pathology; Bleomycin; Bleomycin - toxicity; Citrullination - genetics; Citrulline; Extracellular matrix; Fibroblasts; Fibroblasts - metabolism; Fibrosis; Gene expression; Gene Expression Regulation - genetics; Humanities and Social Sciences; Humans; Inflammation; Kinases; Lung - metabolism; Lung - pathology; Lung diseases; Lung Injury - chemically induced; Lung Injury - complications; Lung Injury - genetics; Lung Injury - pathology; Mice; Mice, Transgenic; Morbidity; multidisciplinary; Phosphatidylinositol 3-Kinases - genetics; Protein-arginine deiminase; Protein-Arginine Deiminase Type 2 - genetics; Proteins; Proteoglycans; Proto-Oncogene Proteins c-akt - genetics; Pulmonary Fibrosis - complications; Pulmonary Fibrosis - drug therapy; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - pathology; Receptor-Like Protein Tyrosine Phosphatases, Class 3; Rheumatoid arthritis; Science; Science (multidisciplinary); Sp1 protein; Sp1 Transcription Factor - genetics; Syndecan; Syndecan-2 - genetics; Therapeutic targets; Transgenic mice
• DOI: 10.1038/s41598-022-06678-7
• EISSN: 2045-2322

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.