Abstract
BackgroundAngiotensin II (Ang II) is associated with rheumatoid arthritis (RA) development. The present study investigated the impact of Ang II on the expression of receptor activator of nuclear factor-κB ligand (RANKL), as well as of nuclear factor of activated T cells cytoplasmic 1 (NFATC1) in RA synovial cells, and explored the underlying mechanism.MethodsThe expression levels of RANKL, NFATC1, and Ang II type 1 receptor (AT1R) were analyzed by RT PCR, western-blot, and/or immunohistochemistry. Western blot was also used to analyze the p38MAPK, JNK, and ERK1/2 pathways.ResultsThe expressions of RANKL and NFATC1 increased in synovial tissues of RA compared to osteoarthritis (OA) synovial tissues. The expression of RANKL was upregulated by Ang II, and this effect was mitigated by an AT1R blocker but not by an AT2R blocker. Furthermore, Ang II activated the ERK1/2, JNK, and p38MAPK pathways, and this effect was blocked by the AT1R blocker. However, ERK1/2 and JNK inhibitors, but not a p38MAPK inhibitor, blocked Ang II-induced RANKL expression. Ang II also increased the level of NFATC1, and this upregulation was attenuated by AT1R blockade, ERK1/2 and JNK inhibition, and siRNA-mediated RANKL silencing, but not by AT2R blockade or p38MAPK inhibition.ConclusionOur results indicated that Ang II activated the ERK1/2 and JNK pathways via AT1R, thus upregulating RANKL and NFATC1 expressions in RA synovial cells.
Highlights
Rheumatoid arthritis (RA) is characterized by progressive destruction of periarticular bone, mainly mediated by osteoclasts, a process that is highly associated with joint deformity and patient disability [1,2,3]
The results showed that Receptor activator of nuclear factor-κB ligand (RANKL) and NFATC1 expressions were higher in the synovial tissues of rheumatoid arthritis (RA) patients than in those of OA patients (Fig. 1a)
Real-time polymerase chain reaction (PCR) confirmed that of RANKL and NFATC1 mRNA levels were significantly higher in the synovial tissues of RA patients compared to those of OA patients (Fig. 1b)
Summary
Rheumatoid arthritis (RA) is characterized by progressive destruction of periarticular bone, mainly mediated by osteoclasts, a process that is highly associated with joint deformity and patient disability [1,2,3]. Many studies have shown that RANKL is expressed and upregulated in the synovial tissues of RA patients and animal models, and that increased RANKL expression in synovial cells is responsible for osteoclastogenesis during RA [3, 7,8,9]. Previous studies have reported that many proinflammatory cytokines, such as interleukin (IL)-18 [11], IL-6 [12], IL-22 [13], and IL-29 [14], may induce RANKL expression in fibroblast-like synoviocytes, the underlying mechanism regulating RANKL expression in RA synovial cells has not been elucidated. The present study investigated the impact of Ang II on the expression of receptor activator of nuclear factor-κB ligand (RANKL), as well as of nuclear factor of activated T cells cytoplasmic 1 (NFATC1) in RA synovial cells, and explored the underlying mechanism
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call