Resveratrol Suppresses Matrix Metalloproteinase-2 Activation Induced by Lipopolysaccharide in Mouse Osteoblasts via Interactions with AMP-Activated Protein Kinase and Suppressor of Cytokine Signaling 1.

Yaqiong Yu,Lihong Qiu,Di Yang,Jiajie Guo,Xiaolin Li,Jing Mi,Liu Qu

doi:10.3390/molecules23092327

Abstract

Porphyromonas endodontalis (P. endodontalis) lipopolysaccharide (LPS) is associated with the progression of bone resorption in periodontal and periapical diseases. Matrix metalloproteinase-2 (MMP-2) expression and activity are elevated in apical periodontitis and have been suggested to participate in bone resorption. Therefore, inhibiting MMP-2 activation may be considered a therapeutic strategy for treating apical periodontitis. Resveratrol is a natural non-flavonoid polyphenol that has been reported to have antioxidant, anti-cancer, and anti-inflammatory properties. However, the capacity of resveratrol to protect osteoblast cells from P. endodontalis LPS insults and the mechanism of its inhibitory effects on MMP-2 activation is poorly understood. Here, we demonstrate that cell viability is unchanged when 10 mg L−1 P. endodontalis LPS is used, and MMP-2 expression is drastically induced by P. endodontalis LPS in a concentration- and time-dependent manner. Twenty micromolar resveratrol did not reduce MC3T3-E1 cell viability. Resveratrol increased AMP-activated protein kinase (AMPK) phosphorylation, and Compound C, a specific AMPK inhibitor, partially abolished the resveratrol-mediated phosphorylation of AMPK. In addition, AMPK inhibition blocked the effects of resveratrol on MMP-2 expression and activity in LPS-induced MC3T3-E1 cells. Treatment with resveratrol also induced suppressor of cytokine signaling 1 (SOCS1) expression in MC3T3-E1 cells. SOCS1 siRNA negated the inhibitory effects of resveratrol on LPS-induced MMP-2 production. Additionally, resveratrol-induced SOCS1 upregulation was reduced by treatment with compound C. These results demonstrate that AMPK and SOCS1 activation are important signaling events during resveratrol-mediated inhibition of MMP-2 production in response to LPS in MC3T3-E1 cells, and there is crosstalk between AMPK and SOCS1 signaling.

Highlights

Apical periodontitis is an inflammatory lesion in periodontal tissues that is caused mostly by bacterial elements derived from an infected root canal system
Gelatin zymography was performed to determine whether P. endodontalis LPS treatment affects Matrix metalloproteinase-2 (MMP-2) activity
We examined whether suppressor of cytokine signaling 1 (SOCS1) induction is involved in the effects of resveratrol

Summary

Introduction

Apical periodontitis is an inflammatory lesion in periodontal tissues that is caused mostly by bacterial elements derived from an infected root canal system. The association between apical periodontitis and cardiovascular diseases has been reported [1]. Porphyromonas endodontalis (P. endodontalis) is a black pigmented Gram-negative anaerobic microorganism, that is a key pathogen in endodontal infections and apical periodontitis, which is attributed to its high prevalence and Molecules 2018, 23, 2327; doi:10.3390/molecules23092327 www.mdpi.com/journal/molecules. Lipopolysaccharide (LPS) produced by P. endodontalis triggers the production of a variety of cytokines that participate in bone destruction in the course of apical periodontitis [5,6,7]. Many studies have demonstrated that MMP-2 expression and activity are elevated in apical periodontitis and have been suggested to play a key role in the progression of this disease [10,11,12]. Abnormally elevated MMP-2 activation must be tightly regulated or properly controlled

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