SIRT2 inhibits oxidative stress and inflammatory response in diabetic osteoarthritis
1Department of Sports Medicine, Affiliated Zhongshan Hospital of Dalian University, Dalian, China. oldpal@126.com.
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.
Insights
Reduced SIRT2 expression worsens diabetic osteoarthritis by increasing oxidative stress and inflammation. Upregulating SIRT2 may alleviate diabetic OA by suppressing these harmful processes.
Area of Science:
- Biochemistry
- Molecular Biology
- Pathology
Background:
- Diabetes mellitus exacerbates osteoarthritis (OA) by disrupting chondrocyte and extracellular matrix homeostasis.
- The interplay between diabetes, inflammation, immunity, and metabolism is crucial in OA pathogenesis.
Purpose of the Study:
- To investigate the role of Sirtuin 2 (SIRT2) in the progression of diabetic OA.
- To elucidate the molecular mechanisms by which SIRT2 influences diabetic OA development.
Main Methods:
- Analysis of SIRT2 expression and histone acetylation in human diabetic OA and normal OA cartilage.
- In vitro studies using chondrocytes (CHs) treated with high glucose to mimic diabetic conditions.
- Assessment of oxidative stress markers (ROS, 8-OH, antioxidant enzymes) and inflammatory mediators (MMP-13, ADAMTS-4, ADAMTS-5) via Western blotting, immunofluorescence, RT-PCR, and flow cytometry.
Main Results:
- Diabetic OA cartilage showed reduced SIRT2 expression and increased histone H3 acetylation (H3K9, H3K14, H3K56).
- High glucose treatment suppressed SIRT2, increased histone acetylation, elevated reactive oxygen species (ROS) and inflammatory markers, while reducing antioxidant enzyme expression in CHs.
- SIRT2 suppression exacerbated high glucose-induced damage, whereas rh-SIRT2 supplementation reversed these detrimental effects.
Conclusions:
- SIRT2 expression diminishes during diabetic OA, correlating with increased histone acetylation, oxidative stress, and inflammation.
- SIRT2 suppression accelerates diabetic OA progression; conversely, SIRT2 upregulation alleviates it by mitigating oxidative stress and inflammation, likely through histone deacetylation.
