The Role of PPARγ in Advanced Glycation End Products-Induced Inflammatory Response in Human Chondrocytes

Abstract

ObjectiveAdvances made in the past ten years highlight the notion that peroxisome proliferator-activated receptors gamma (PPARγ) has protective properties in the pathophysiology of osteoarthritis (OA). The aim of this study was to define the roles of PPARγ in AGEs-induced inflammatory response in human chondrocytes.MethodsPrimary human chondrocytes were stimulated with AGEs in the presence or absence of neutralizing antibody against RAGE (anti-RAGE), MAPK specific inhibitors and PPARγ agonist pioglitazone. The expression of IL-1, MMP-13, TNF-α, PPARγ, nuclear NF-κB p65 and cytosol IκBα was determined by western blotting and real-time PCR.ResultsAGEs could enhance the expression of IL-1, TNF-α, and MMP-13, but the level of PPARγ was decreased in a time- and dose-dependent manner, which was inhibited by anti-RAGE, SB203580 (P38 MAPK specific inhibitor) and SP600125 (a selective inhibitor of JNK). PPARγ agonist pioglitazone could inhibit the effects of AGEs-induced inflammatory response and PPARγ down-regulation. In human chondrocytes, AGEs could induce cytosol IκBα degradation and increase the level of nuclear NF-κB p65, which was inhibited by PPARγ agonist pioglitazone.ConclusionsIn primary human chondrocytes, AGEs could down-regulate PPARγ expression and increase the inflammatory mediators, which could be reversed by PPARγ agonist pioglitazone. Activation of RAGE by AGEs triggers a cascade of downstream signaling, including MAPK JNK/ p38, PPARγ and NF-κB. Taken together, PPARγ could be a potential target for pharmacologic intervention in the treatment of OA.

Effect of PPARG on AGEs‐induced AKT/MTOR signaling‐associated human chondrocytes autophagy

“…But have not reported the molecular mechanism of AGEs-induced autophagy. In our previous research (Chen et al, 2014;Li et al, 2016;Ma et al, 2015;Zhang et al, 2016), we found that AGEs downregulate PPARG exression while pioglitazone inhibits the AGEsinduced inflammatory response and apoptosis in human primary chondrocytes in vitro and in vivo. Pioglitazone also inhibits the development of AGEs-induced arthritis in rabbit and mouse models.…”

“…AGEs are the end products of the non‐enzymatic glycosylation reactions with glucose, other sugars, proteins, lipids, and nucleic acids (Loeser et al, ). Expression of receptor for AGEs (RAGE) has been shown to trigger the expression of IL‐1, IL‐6, TNF‐α, and MMP‐13 (Chen et al, ; Ma et al, ; Li et al, ). Our previous research has shown that AGEs induce apoptosis of chondrocytes (Zhang et al, ).…”

“…Peroxisome proliferator‐activated receptor‐γ (PPARG), a superfamily of nuclear receptors, is a new therapeutic target for OA (Giaginis et al, ). This type of receptor has been shown to be ligand‐activated and exhibit anti‐inflammatory and anticatabolic properties in vitro and in vivo (Chen et al, ; Ma et al, ; Li et al, ; Zhang et al, ); agonists of PPARG impart OA protection in animal models. Considerable evidence has shown that PPARG is involved in the regulation of MTOR/autophagy signaling in articular cartilage (Vasheghani et al, ).…”

The Role of Inflammation in the Pathogenesis of Osteoarthritis

“…Cytokines secreted by the immune cells are the main players of any inflammatory conditions, including osteoarthritis [7]. Proinflammatory cytokines, such as IL-1β and TNF-α, are among the mediators secreted in early osteoarthritis [20][21][22][23]. IL-1β and TNF-α drive the inflammatory cascade independently or in collaboration with other cytokines [24].…”

Morin Exhibits Anti-Inflammatory Effects on IL-1β-Stimulated Human Osteoarthritis Chondrocytes by Activating the Nrf2 Signaling Pathway

“…The cells were cultured with DMEM containing 10% FBS at 37°C with 5% CO 2 . The medium was changed every 2 days and passage 2 to 4 were used in the present study [21].…”