Implication of SIRT6 in the Pathogenesis of Rheumatoid Arthritis
Date Issued
2010
Date
2010
Author(s)
Hung, Meng-Hao
Abstract
Rhumatoid arthritis (RA) is a systemic, chronic autoimmune disorder, and is characterized by progressive destruction of normal joint soft tissue, bone erosion, and eventually joint deformity. The prevalence of RA in temporalmandibular joint is about 14~85%, and there are about 100,000 affected cases in Taiwan.
Cyr61, a cystine-rich protein, found to be play an important role in RA patients. CCN1 was known to be associated with angiogenesis, inflammation, cell and tumor growth. Literature review showed compared with the healthy co-twin, higher level of Cyr61 in RA patients with cDNA micro-array analysis of B cells. Cyr 61 also recruit inflammatory cell & marchpharge to inflammatory sites, induce angiogenesis, but the mechanism still remained unknown.
In literature review, Cyr61 may stimulates Monocyte chemoattractant protein 1 (CCL2/MCP-1) to promote macrophage hemotaxis was noticed. Our previous experients also showed that Cyr61 can enhance CCL2/MCP-1 expression in U2OS cells (a a osteosarcoma cell line with osteoblastic phenotype). Our previous data also showed that Cyr61 expression may be regulated via phosphoraton of CREB(c-AMP responsive element binding protein)
SIRT6, a member of the sirtuin (SIRT) family, is a NAD-dependent deacetylase that promote longevity in multiple organisms. SIRT may regulate different gene expression through interaction with histone. Lack of SIRT6 leads to shortened life span and an aging-like phenotype in mice. Kawahara et al. noticed that SIRT6 attenuates NF-kB signaling through histone deacetylation (cell 2009). NFκB, a signaling pathway known to be associated with aging and inflammation, indicated that SIRT6 is thought to be related with inflammation and we wondered if SIRT6 could regulate Cyr61 expression.
Human specimen of RA patient were examined with Immunochemistry stain. To examine the effects of pro-inflammatory cytokines on Cyr61 expression in osteoblastic cells and the modulatory action of SIRT6, A U2OS cell stable clone regularly expressed SIRT6 was selected. The role of cAMP response element (CRE)-binding protein (CREB) in Cyr61 induction was assessed, and western blot were used to check the expression level of Cyr61 and Phospho-CREB. Luciferase assay was used to check the Cyr61 activity; ELISA for secreted MCP-1 were also examinated. In a rat model of collagen-induced arthritis (CIA), the relation of osteoblastic expression of Cyr61 and SIRT6 to disease progression was evaluated.
RESULT: Lower Cyr61 expression level were noticed after treated with TNFa in SIRT6-expressing U2OS group, and lower phosphor-CREB level were also noticed. In luciferase assay, SIRT6 also lower Cyr61 promoter activity, indicates that SIRT6 regulates Cyr61 expression through CREB phosphorylation. In Human RA tissue andrat CIA model, Cyr61 were found in tissue with more severe inflammation activity, and SIRT6 were found in tissue with a bone-remodeling pattern. There seemed to be a opposite tendency between SIRT6 and Cyr61 expression.
CONCLUSION: In vitro, SIRT6 regulates Cyr61 expression via inhibit CREB activation; in vivo, Cyr61 were expressed in tissue with more severe inflammation and SIRT6 were found in tissue with a higher bone remodeling ability. The interaction between Cyr61 and SIRT6 needs further investigation.
Subjects
SIRT6
Cyr61
CREB
Rhumatoid artheritis
SDGs
Type
thesis
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