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Activation of the cannabinoid receptor 1 by ACEA suppresses senescence in human primary chondrocytes through sirt1 activation.

ABSTRACT: Senescence of chondrocytes and cartilage degeneration induced by the proinflammatory cytokine interleukin-1? is associated with the pathogenesis of osteoarthritis. The cannabinoid receptor 1 has been involved in the pathological development of various diseases. Here, we evaluated whether activation of cannabinoid receptor 1 using its selective agonist arachidonyl-2-chloroethylamide had an influence on cellular senescence induced by interleukin-1?in human chondrocytes. Our findings demonstrate that agonist arachidonyl-2-chloroethylamidedecreased senescence-associated ?-galactosidase activity and cell cycle arrest in the G0/G1 phase induced by interleukin-1?. Importantly, our results display interleukin-1?treatment significantly increased the expressions of senescence genes (caveolin-1, PAI-1 and p21), which were prevented by agonist arachidonyl-2-chloroethylamide treatment. However, it was noticed that these functions of agonist arachidonyl-2-chloroethylamide were abolished by the cannabinoid receptor 1 selective antagonist AM251, suggesting the involvement of cannabinoid receptor 1. Also, our results indicate that agonist arachidonyl-2-chloroethylamide enhanced the expression of sirt1. These findings suggest that activation of cannabinoid receptor 1 by agonist arachidonyl-2-chloroethylamide might have a protective effect against pro-inflammatory cytokines such as interleukin-1?-induced chondrocytes senescence in osteoarthritis patients. Impact statement Senescence of chondrocytes and cartilage degeneration induced by the proinflammatory cytokine interleukin-1? (IL-1?) are associated with the pathogenesis of osteoarthritis (OA). Here we found that: (a) the CB1 agonist ACEA abolished IL-1?-induced senescence and cell arrest in chondrocytes; (b) the CB1 agonist ACEA also abolished IL-1?-induced expression of caveolin-1, PAI-1, and p21;

SUBMITTER: Zhang D

PROVIDER: S-EPMC5882028 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Activation of the cannabinoid receptor 1 by ACEA suppresses senescence in human primary chondrocytes through sirt1 activation.

Zhang Dawei D Zhang Gang G Li Zongyu Z Li Bingsheng B

Experimental biology and medicine (Maywood, N.J.) 20180214 5

Senescence of chondrocytes and cartilage degeneration induced by the proinflammatory cytokine interleukin-1β is associated with the pathogenesis of osteoarthritis. The cannabinoid receptor 1 has been involved in the pathological development of various diseases. Here, we evaluated whether activation of cannabinoid receptor 1 using its selective agonist arachidonyl-2-chloroethylamide had an influence on cellular senescence induced by interleukin-1βin human chondrocytes. Our findings demonstrate th ...[more]

PMID: 29444596

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Project description:There is growing evidence in support of the involvement of inflammatory response in the pathogenesis of osteoarthritis (OA). Harpagoside, one of the bioactive components of Harpagophytum procumbens (Hp), has been shown to possess anti-inflammatory properties. Here we used an in vitro model of inflammation in OA to investigate the potential of harpagoside to suppress the production of inflammatory cytokines/chemokines such as IL-6 and matrix degrading proteases. We further investigated the likely targets of harpagoside in primary human OA chondrocytes. OA chondrocytes were pre-treated with harpagoside before stimulation with IL-1?. mRNA expression profile of 92 cytokines/chemokines was determined using TaqMan Human Chemokine PCR Array. Expression levels of selected mRNAs were confirmed using TaqMan assays. Protein levels of IL-6 and MMP-13 were assayed by ELISA and immunoblotting. Total protein levels and phosphorylation of signaling proteins were determined by immunoblotting. Cellular localization of IL-6 and c-Fos was performed by immunofluorescence and confocal microscopy. DNA binding activity of c-FOS/AP-1 was determined by ELISA. Harpagoside significantly altered the global chemokine expression profile in IL-1?-stimulated OA chondrocytes. Expression of IL-6 was highly induced by IL-1?, which was significantly inhibited by pre-treatment of OA chondrocytes with harpagoside. Harpagoside did not inhibit the IL-1?-induced activation of NF-?B and C/EBP? transcription factors but suppressed the IL-1?-triggered induction, phosphorylation, and DNA binding activity of c-FOS, one of the main components of AP-1 transcription factors. Further, harpagoside significantly inhibited the expression of MMP-13 in OA chondrocytes under pathological conditions. siRNA-mediated knockdown of IL-6 resulted in suppressed expression and secretion of MMP-13 directly linking the role of IL-6 with MMP-13 expression. Taken together, the present study suggests that harpagoside exerts a significant anti-inflammatory effect by inhibiting the inflammatory stimuli mediated by suppressing c-FOS/AP-1 activity in OA chondrocytes under pathological conditions. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:311-320, 2017.

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Activation of the cannabinoid receptor 1 by ACEA suppresses senescence in human primary chondrocytes through sirt1 activation.

Publications

Activation of the cannabinoid receptor 1 by ACEA suppresses senescence in human primary chondrocytes through sirt1 activation.

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