SIRT6 regulates the cigarette smoke-induced signalling in rheumatoid arthritis synovial fibroblasts

Engler, Andrea; Niederer, Fabienne; Klein, Kerstin; Kyburz, Diego; Camici, Giovanni G.; Ospelt, Caroline

doi:10.1007/s00109-014-1139-0

Cited by 34 publications

(16 citation statements)

References 32 publications

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“…However, when exposed to risk factors, such as smoking or ageing, Sirt3 knockout mice will have high oxidative stress level and may be more sensitive to osteoporosis Among the Sirtuin family, Sirt1, Sirt2, and Sirt6 are reported to regulate bone homeostasis in vivo [24][25][26]. Sirt1 regulates differentiation of MSCs and represses osteoblast injury [27,28], while Sirt2 and Sirt6 protect mice from arthritis [25,26]. Sirt3 is the first mitochondrial Sirtuin that has been shown to participate in maintaining bone hemostasis.…”

Section: Discussionmentioning

confidence: 99%

Sirt3–MnSOD axis represses nicotine-induced mitochondrial oxidative stress and mtDNA damage in osteoblasts

Yong

Shen

et al. 2015

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Increasing evidence has suggested an important role played by reactive oxygen species in the pathogenesis of osteoporosis. Tobacco smoking is an important risk factor for the development of osteoporosis, and nicotine is one of the major components in tobacco. However, the mechanism by which nicotine promotes osteoporosis is not fully understood. Here, in this study, we found that nicotineinduced mitochondrial oxidative stress and mitochondrial DNA (mtDNA) damage in osteoblasts differentiated from mouse mesenchymal stem cell. The activity of MnSOD, one of the mitochondrial anti-oxidative enzymes, was significantly reduced by nicotine due to the reduced level of Sirt3. Moreover, it was also found that Sirt3 could promote MnSOD activity by deacetylating MnSOD. Finally, Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP, a MnSOD mimetic) was found to markedly reduce the effect of nicotine on osteoblasts. In summary, Sirt3-MnSOD axis was identified as a negative component in nicotine-induced mitochondrial oxidative stress and mtDNA damage, and MnTBAP may serve as a potential therapeutic drug for osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Sirt3–MnSOD axis represses nicotine-induced mitochondrial oxidative stress and mtDNA damage in osteoblasts

Yong

Shen

et al. 2015

ABBS

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“…To induce lung emphysema and COPD in an animal model, mice were exposed to cigarette smoke from research cigarettes (1R4F, University of Kentucky, USA) for 5 days per week as described elsewhere [16]. After 3 weeks mice were euthanized and total RNA including miRNAs from lung tissue was isolated.…”

Section: Experimental In Vivo Modelsmentioning

confidence: 99%

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

et al. 2016

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Reduced activity of histone deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here, we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics. Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD, miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved in anti-miR-223-treated cells. Direct miRNAtarget interaction was confirmed by reporter gene assay. In a next step, reduced expression of HDAC2 was found to increase the levels of the chemokine fractalkine (CX3CL1). In vivo studies confirmed elevated expression levels of miR-223 in mice exposed to cigarette smoke and in emphysematous lung tissue from LPS-treated mice. Moreover, a significant inverse correlation of miR-223 and HDAC2 expression was found in two independent cohorts of COPD patients. These data emphasize that miR-223, the most prevalent miRNA in COPD, controls expression and activity of HDAC2 in pulmonary cells, which, in turn, might alter the expression profile of chemokines. This pathway provides a novel pathogenic link between dysregulated miRNA expression and epigenetic activity in COPD. KEY MESSAGES: Histone deacetylase 2 is directly targeted by miR-223. Levels of miR-223 are induced by interleukin-1 and tumor necrosis factor-. miR-223 controls the expression of fractalkine by targeting histone deacetylase 2. miR-223 levels are increased in COPD mouse models. miR-223 levels inversely correlate with HDAC2 expression in COPD patients. AbstractReduced activity of Histone Deacetylase 2 (HDAC2) has been described in patients with chronic obstructive pulmonary disease (COPD) but the mechanisms resulting in decreased expression of this important epigenetic modifier remain unknown. Here we employed several in vitro experiments to address the role of microRNAs (miRNAs) on the regulation of HDAC2 in endothelial cells. Manipulation of miRNA levels in human pulmonary artery endothelial cells (HPAEC) was achieved by using electroporation with anti-miRNAs and miRNA mimics.Target prediction software identified miR-223 as a potential repressor of HDAC2. In subsequent stimulation experiments using inflammatory cytokines known to be increased in patients with COPD miR-223 was found to be significantly induced. Functional analysis demonstrated that overexpression of miR-223 decreased HDAC2 expression and activity in HPAEC. Conversely, HDAC2 expression and activity was preserved i...

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“…Similarly, Sirt6 suppresses inflammation and bone resorption in the CIA model [67•]. Consistently, Engler et al showed that cigarette smoking, a risk factor for RA development, increased SIRT6 levels in RA synovial fibroblasts and correlated with attenuated MMP-1 production [68], supporting the anti-inflammatory effects exerted by SIRT6.…”

Section: Sirt2-7 In Oa and Cartilage Biologymentioning

confidence: 72%

The Role of Sirtuins in Cartilage Homeostasis and Osteoarthritis

2016

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The past decade has witnessed many advances in the understanding of sirtuin biology and related regulatory circuits supporting the capacity of these proteins to serve as energy-sensing molecules that contribute to healthspan in various tissues, including articular cartilage. Hence, there has been a significant increase in new investigations that aim to elucidate the mechanisms of sirtuin function and their roles in cartilage biology, skeletal development, and pathologies such as osteoarthritis (OA), rheumatoid arthritis (RA), and intervertebral disc degeneration (IVD). The majority of the work carried out to date has focused on SIRT1, although SIRT6 has more recently become a focus of some investigations. In vivo work with transgenic mice has shown that Sirt1 and Sirt6 are essential for maintaining cartilage homeostasis and that the use of sirtuin-activating molecules such as resveratrol may have beneficial effects on cartilage anabolism. Current thinking is that SIRT1 exerts positive effects on cartilage by encouraging chondrocyte survival, especially under stress conditions, which may provide a mechanism supporting the use of sirtuin small-molecule activators (STACS) for future therapeutic interventions in OA and other degenerative pathologies of joints, especially those that involve articular cartilage.

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SIRT6 regulates the cigarette smoke-induced signalling in rheumatoid arthritis synovial fibroblasts

Abstract: Cigarette smoke induces pro-inflammatory and matrix-destructive responses in RASF. Cigarette smoke enhances the expression of SIRT6 in vitro and in vivo. TNFα increases the levels of SIRT6. SIRT6 diminishes MMP1 production under cigarette smoke extract and TNFα stimulation.

Cited by 34 publications

References 32 publications

Sirt3–MnSOD axis represses nicotine-induced mitochondrial oxidative stress and mtDNA damage in osteoblasts

Sirt3–MnSOD axis represses nicotine-induced mitochondrial oxidative stress and mtDNA damage in osteoblasts

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

The Role of Sirtuins in Cartilage Homeostasis and Osteoarthritis

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SIRT6 regulates the cigarette smoke-induced signalling in rheumatoid arthritis synovial fibroblasts

Abstract: Cigarette smoke induces pro-inflammatory and matrix-destructive responses in RASF. Cigarette smoke enhances the expression of SIRT6 in vitro and in vivo. TNFα increases the levels of SIRT6. SIRT6 diminishes MMP1 production under cigarette smoke extract and TNFα stimulation.

Cited by 34 publications

References 32 publications

Sirt3&ndash;MnSOD axis represses nicotine-induced mitochondrial oxidative stress and mtDNA damage in osteoblasts

Sirt3&ndash;MnSOD axis represses nicotine-induced mitochondrial oxidative stress and mtDNA damage in osteoblasts

MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD

The Role of Sirtuins in Cartilage Homeostasis and Osteoarthritis

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Product

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Sirt3–MnSOD axis represses nicotine-induced mitochondrial oxidative stress and mtDNA damage in osteoblasts

Sirt3–MnSOD axis represses nicotine-induced mitochondrial oxidative stress and mtDNA damage in osteoblasts