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Syndecan-2 regulates PAD2 to exert antifibrotic effects on RA-ILD fibroblasts
- Source :
- Scientific reports. 12(1)
- Publication Year :
- 2021
-
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 :
- Sp1 Transcription Factor
Pulmonary Fibrosis
Receptor-Like Protein Tyrosine Phosphatases, Class 3
Mice, Transgenic
Lung Injury
Fibroblasts
Anti-Citrullinated Protein Antibodies
Arthritis, Rheumatoid
Bleomycin
Mice
Phosphatidylinositol 3-Kinases
Gene Expression Regulation
Protein-Arginine Deiminase Type 2
Animals
Humans
Citrullination
Syndecan-2
Lung
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 12
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific reports
- Accession number :
- edsair.pmid..........437e479d8790048d92a5b1660f1ffdab