Abstract
This study was performed to elucidate the molecular function of the synoviocyte proliferation-associated in collagen-induced arthritis (CIA) 1/serum amyloid A-like 1 (SPACIA1/SAAL1) in mice CIA, an animal model of rheumatoid arthritis (RA), and human RA-synovial fibroblasts (RASFs). SPACIA1/SAAL1-deficient mice were generated and used to create mouse models of CIA in mild or severe disease conditions. Cell cycle-related genes, whose expression levels were affected by SPACIA1/SAAL1 small interfering RNA (siRNA), were screened. Transcriptional and post-transcriptional effects of SPACIA1/SAAL1 siRNA on cyclin-dependent kinase (cdk) 6 gene expression were investigated in human RASFs. SPACIA1/SAAL1-deficient mice showed later onset and slower progression of CIA than wild-type mice in severe disease conditions, but not in mild conditions. Expression levels of cdk6, but not cdk4, which are D-type cyclin partners, were downregulated by SPACIA1/SAAL1 siRNA at the post-transcriptional level. The exacerbation of CIA depends on SPACIA1/SAAL1 expression, although CIA also progresses slowly in the absence of SPACIA1/SAAL1. The CDK6, expression of which is up-regulated by the SPACIA1/SAAL1 expression, might be a critical factor in the exacerbation of CIA.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and hyperplasia [1,2]
We identified synoviocyte proliferation-associated in collagen-induced arthritis (CIA) 1/serum amyloid A-like 1 (SPACIA1/SAAL1) as an overexpressed gene in the joint tissue of mice with CIA and indicated that the gene was associated with abnormal synovial proliferation in human RA [7]
In mild CIA, SPACIA1-overexpressing mice showed early onset and rapid progression of CIA. These results indicate that endogenous SPACIA1 expression in wt mice reached a plateau in severe CIA, but not in mild CIA
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and hyperplasia [1,2]. A major component of the hyperplastic synovial lining, are important in the pathogenesis of synovitis because they secrete cytokines and chemokines, leading to exacerbation of inflammation. Immuno-suppressive biologics such as tumor necrosis factor (TNF) inhibitors with methotrexate (MTX) have become an important part of the standard care for RA [3]. It is assumed that the anti-proliferative effects of MTX may not work in RA [4]. Other studies have shown the potential of an anti-proliferative strategy using a kinase inhibitor of both cyclin-dependent kinase (CDK) 4 and CDK6, cyclin D partners in the cell cycle, in some mouse models of RA [5,6]. We believe that the abnormal synovial proliferation in RA should be a crucial target for drug discovery
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