Abstract
BackgroundSirtuin 1 (Sirt1) is a nuclear enzyme from the class III histone deacetylases that modulates gene expression and is involved in bone and cartilage remodeling. The goal of our study was to evaluate Sirt1 activity in peripheral blood mononuclear cells in patients with osteoarthritis in comparison with control patients, and to determine the relationship between Sirt1 activity and production of TNFα, IL-6 and IL-8 by peripheral blood mononuclear cells after ex vivo treatment with resveratrol, a Sirt1 activator.ResultsA prospective study was performed to compare the activity of Sirt1 in patients with primary osteoarthritis of the knee (American College of Rheumatology criteria) with its activity in controls. Peripheral blood mononuclear cells were isolated from peripheral blood, and Sirt1 activity evaluated from cytoplasmic and nuclear compartments using a fluorometric assay. Culture supernatant levels of TNFα, IL-6, and IL-8 were quantified before and after resveratrol ex vivo treatment. Nineteen patients with symptomatic knee osteoarthritis (age 64 ±9 years) and 18 controls (age 54 ±13 years) were included. No differences were found in cytoplasmic or nuclear Sirt1 activity between patients and controls. After resveratrol treatment, no changes in TNFα or IL-8 levels were found, but a significant dose-dependent increase in IL-6 levels was demonstrated in patients with osteoarthritis, but not controls. Sirt1 activity did not correlate with clinical activity (Lequesne’s index) or inflammation (erythrocyte sedimentation rate, C-reactive protein).ConclusionSirt1 activity (cytoplasmic and nuclear) from peripheral blood mononuclear cells did not differ between patients with osteoarthritis and controls. Ex vivo treatment of peripheral blood mononuclear cells with resveratrol was associated with a dose-dependent increase in IL-6 levels only in patients with osteoarthritis.
Highlights
Sirtuin 1 (Sirt1) is a nuclear enzyme from the class III histone deacetylases that modulates gene expression and is involved in bone and cartilage remodeling
In agreement with the upregulation of both Sirt1 protein expression and Sirt1 activity by resveratrol in several cell types [14,15], we observed a similar increase of both Sirt1 protein expression and activity in peripheral blood mononuclear cells (PBMCs) isolated from healthy donors and treated with resveratrol (Figure 3)
No changes in Tumor necrosis factor-alpha (TNFα) or IL-8 levels were found, but a significant dose-dependent increase in IL-6 levels in the supernatants of PBMCs cultured for 48 h was demonstrated in patients with OA (P = 0.02; Figure 4), but not in controls
Summary
Sirtuin 1 (Sirt1) is a nuclear enzyme from the class III histone deacetylases that modulates gene expression and is involved in bone and cartilage remodeling. OA is a polygenic disease [1], but epigenetic effects are important mediators of OA biology [2], including DNA methylation and histone apoptosis [6,7] and enhances survival of osteoarthritic chondrocytes [8], and may be implicated in the pathogenesis of OA [9]. This ‘protective’ role of Sirt is reduced by proinflammatory cytokines such as TNFα, leading to inactivation of Sirt in human osteoarthritic chondrocytes [10]. Activation of Sirt by resveratrol has been demonstrated in articular chondrocytes [12], and resveratrol may have a positive effect on cartilage protection and apoptosis inhibition [13]
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