SIRT2 inhibits oxidative stress and inflammatory response in diabetic osteoarthritis

Z.-A. Qu, X.-J. Ma, S.-B. Huang, X.-R. Hao, D.-M. Li, K.-Y. Feng, W.-M. Wang

Department of Sports Medicine, Affiliated Zhongshan Hospital of Dalian University, Dalian, China. oldpal@126.com

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• Orthopedics

OBJECTIVE: Diabetes mellitus is involved in inflammation, immunity, and metabolism during osteoarthritis (OA). It destroys the normal synthesis and degradation balance of chondrocytes (CHs) and extracellular matrix (ECM). The purpose of this study was to explore the possible way of SIRT2 influencing the progress of diabetic OA.

PATIENTS AND METHODS: Proteins of diabetic OA and normal OA cartilage samples were extracted from patients undergoing knee joint operation. CHs were also isolated from the cartilage exempted from diabetes for cell culture. Glucose was used to treat CHs for imitating the microenvironment of diabetes. The expressions of SIRT2, acetylated H3K9, H3K14, and H3K56 protein were determined by Western blotting. SIRT2, 8-hydroxy-2’ deoxyguanosine (8-OH), and MMP-13 expressions were analyzed using immunofluorescence. RT-PCR was performed to measure the mRNA levels of SOD1, SOD2, CAT, MMP-13, ADAMTS-4, and ADAMTS-5. Total ROS level was performed by flow cytometry assay.

RESULTS: SIRT2 expression was reduced, whereas acetylated H3K9, H3K14, and H3K56 were upregulated in diabetic cartilage compared to normal. High glucose suppressed the expression of SIRT2 but accelerated the acetylation of H3K9, H3K14, and H3K56. Besides, high glucose promoted the expression of 8-OH, and inhibited SOD1, SOD2, and CAT mRNA expressions, resulting in the up-regulated ROS level of CHs. In addition, high glucose activated the inflammatory response by upregulation of MMP-13, ADAMTS-4, and ADAMTS-5 expressions. SirReal2 suppressed SIRT2 and resulted in several acetylations of H3, more ROS, less antioxidant enzymes, and stronger inflammatory response caused by high glucose. However, supplied rh-SIRT2 reversed these negative effects of high glucose in CHs.

CONCLUSIONS: SIRT2 expression is reduced along with the diabetic OA process with increased acetylation of H3, oxidative stress, and inflammatory response. Suppression of SIRT2 accelerates the progress of diabetic OA and upregulation of SIRT2 alleviates diabetic OA development by suppressing oxidative stress and inflammatory response that are likely to be related to the deacetylation of H3.

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