Abstract
Rheumatoid arthritis (RA) is an autoimmune disease of the joints characterized by synovial hyperplasia and chronic inflammation. Fibroblast-like synoviocytes (FLS) play a central role in RA initiation, progression, and perpetuation. Prior studies showed that sirtuin 1 (SIRT1), a deacetylase participating in a broad range of transcriptional and metabolic regulations, may impact cell proliferation and inflammatory responses. However, the role of SIRT1 in RA–FLS was unclear. Here, we explored the effects of SIRT1 on the aggressiveness and inflammatory responses of cultured RA-FLS. SIRT1 expression was significantly lower in synovial tissues and FLS from RA patients than from healthy controls. Overexpression of SIRT1 significantly inhibited RA-FLS proliferation, migration, and invasion. SIRT1 overexpression also significantly increased RA-FLS apoptosis and caspase-3 and -8 activity. Focusing on inflammatory phenotypes, we found SIRT1 significantly reduced RA-FLS secretion of TNF-α, IL-6, IL-8, and IL-1β. Mechanistic studies further revealed SIRT1 suppressed NF-κB pathway by reducing p65 protein expression, phosphorylation, and acetylation in RA-FLS. Our results suggest SIRT1 is a key regulator in RA pathogenesis by suppressing aggressive phenotypes and inflammatory response of FLS. Enhancing SIRT1 expression or function in FLS could be therapeutic beneficial for RA by inhibiting synovial hyperplasia and inflammation.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia, inflammation and progressive destruction of the cartilage and bone, which lead to irreversible joint deformities and functional loss
To test potential association between sirtuin 1 (SIRT1) and RA, we first measured the expression level of SIRT1 mRNA in the synovial tissues and Fibroblast-like synoviocytes (FLS) obtained from 6 negative control individuals and 12 RA patients by quantitative reverse transcription–PCR (RT-qPCR)
In order to systematically study the role of SIRT1 in RA-FLS, primary RA-FLS culture was established using cells isolated from RA patients
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia, inflammation and progressive destruction of the cartilage and bone, which lead to irreversible joint deformities and functional loss. The cause of RA is unclear, many risk factors are recognized including genetics, environment, hormones, and lifestyle [1]. RA is a progressive disease that often develops systemic complications, including cardiovascular, pulmonary, skeletal, and psychological disorders. Current treatment for RA relies on conventional and biologic disease-modifying antirheumatic drugs, which often lead to toxicity and only partial responses. RA is one of the most common autoimmune disorders affecting 1% of the global population [3]. The development of efficacious RA therapies remains an urgent public health need
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