Syndecan‐4 involves in the pathogenesis of rheumatoid arthritis by regulating the inflammatory response and apoptosis of fibroblast‐like synoviocytes

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and the pathogenesis of RA is still unknown. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) are of significance in the pathogenesis of RA. In this study, three microarray profiles (GSE55457, GSE55584, and GSE55235) of human joint FLSs from 33 RA patients and 20 normal controls were extracted from the Gene Expression Omnibus Dataset and analyzed to investigate the underlying pathogenesis of RA. As analyzed by the differently expressed genes, gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and protein-protein interaction network analysis, syndecan-4 (SDC4), a receptor of multiple cytokines and chemokines, which played a key role in the regulation of inflammatory response, was found to be an essential regulator in RA. To further validate these results, the levels of SDC4, reactive oxygen species (ROS), nitric oxide (NO), inflammation, and apoptosis in RA-FLSs were examined. SDC4-silenced RA-FLSs were also used. The results demonstrated that SDC4 and the level of ROS, NO, and inflammation were highly expressed while the apoptosis was decreased in RA-FLSs compared with normal FLSs. SDC4 silencing significantly suppressed the levels of ROS, NO, and inflammation; elevated the expression of nuclear factor erythroid 2-related factor 2; and promoted the apoptosis of RA-FLSs. Collectively, our results demonstrated a new mechanism of SDC4 in initiating the inflammation and inhibiting the apoptosis of RA-FLSs and that a potential target for the diagnosis and treatment of RA in the clinic might be developed. K E Y W O R D Sapoptosis, fibroblast-like synoviocytes, inflammation, rheumatoid arthritis, syndecan-4

RAB5A is associated with genes involved in exosome secretion: Integration of bioinformatics analysis and experimental validation

“…In static PPI network analysis, several thresholds of STRING combined scores (0.4, 0.7, and 0.9) are routinely considered as a cut‐off value. In this regard, more authentic PPI studies often use interactions with the combined scores of 0.4 and more to identify significant modules; 63–66 while others use 0.7 and 0.9 as a significant cut‐off value 67,68 . To solve this discrepancy, altering the expression of several genes with different combined scores was investigated in response to RAB5A knockdown.…”

Proteoglycans in Obesity-Associated Metabolic Dysfunction and Meta-Inflammation

“…This will either attenuate or propagate HSBP functions, including properties of chemokines/cytokines and their interactions with leukocytes and endothelial cells (Figure 2) (31,34). Several in vitro and in vivo studies have highlighted the diverse roles of SDCs in inflammation (31,34,72), but reports investigating the impact of SDCs on obesity-related metabolic inflammation are sparse (73)(74)(75)(76)(77). Using whole-genome linkage studies a SNP in chromosomal region 20q12-13, which contains the SDC4 gene, has been linked with increased predisposition for T2D and obesity (78,79).…”

The correlation of syndecan-4 with disease activity and serological characteristics of rheumatoid arthritis

“…The apoptosis of RA-broblast-like synoviocytes (FLSs) regulated by syndecan-4 was mainly through the intrinsic pathway in which the P53, Caspase-3, B-cell leukemia/lymphoma 2 (Bcl2), and Bcl2-associated X protein (Bax) were involved. It provided evidence that Syndecan-4 mediated the in ammation and apoptosis of RA-FLSs by mediating the ROS and NO release [11].…”

“…A previous study reported little staining for syndecan-4 in synovium of early RA [12]. A most recent study demonstrated that highly expressed syndecan-4 was associated with decreased apoptosis in RA-FLS [11].…”