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

Abstract

Accumulation of advanced glycation end products (AGEs) in articular cartilage is thought to represent a major risk factor for osteoarthritis development. In this study we aimed to probe the role of AGEs in human chondrocytes and to determine the impact of the peroxisome proliferator-activated receptor-γ (PPARG) on AGEs-induced cell autophagy. Cell viability was measured after human chondrocytes were treated with different concentrations of AGEs with or without the PPARG inhibitor, T0070907, or agonist, pioglitazone. Autophagy activation markers (MAP2LC3, BECN1 and SQSTM1/P62), expression of PPARG and the phosphorylation levels of Akt/MTOR were determined by Western blotting; autophagosome formation was analyzed by transmission electron microscopy (TEM); autophagic flux was detected with mRFP-GFP-LC3 tandem construct. Low doses of AGEs over a short amount of time stimulated chondrocyte proliferation and autophagy by limiting phosphorylation of Akt/MTOR signaling. The addition of PPARG inhibitor T0070907 lead to defective autophagy. High dose and long exposure to AGEs inhibited cell viability and autophagy by increasing phosphorylation levels of Akt/MTOR signaling. The agonist, pioglitazone, was shown to protect cell autophagy in a dose-dependent manner. Our findings suggest AGEs can downregulate PPARG and that PPARG maintains cell viability by activating the Akt/MTOR signaling pathway as well as inducing chondrocyte autophagy.

PPARγ preservation via promoter demethylation alleviates osteoarthritis in mice

“…In addition, 5Aza significantly alleviated the abnormal expression of Adamts5, MMP13, Collagen2 and Aggrecan in IL-1β-treated chondrocytes (figure 4B). Intriguingly, the beneficial effects were largely abolished in presence of a specific PPARγ inhibitor T007090736 (figure 4C,D), suggesting that 5Aza restoration of PPARγ contributes significantly to the chondro-protective effects.…”

Transplantation of Human Urine-Derived Stem Cells Ameliorates Erectile Function and Cavernosal Endothelial Function by Promoting Autophagy of Corpus Cavernosal Endothelial Cells in Diabetic Erectile Dysfunction Rats

“…For group (5), 3-MA was added into the lower chambers for 24 h. All experiments were performed in triplicate. The concentration of AGEs (200 μ g/ml) and 3-MA (2 mM) used in the present study was referred to previous studies [33–35].…”

Pyridinecarboxylic Acid Derivative Stimulates Pro-Angiogenic Mediators by PI3K/AKT/mTOR and Inhibits Reactive Nitrogen and Oxygen Species and NF-κB Activation Through a PPARγ-Dependent Pathway in T. cruzi-Infected Macrophages

“…Recently, it has been demonstrated that canonical PI3Kγ signaling in myeloid cells is essential to restrict T. cruzi heart parasitism and ultimately to avoid myocarditis, heart damage, and death in mice (23). Furthermore, in a human in vitro model of osteoarthritis characterized by increased advanced glycation end (AGE) products accumulation and reduced autophagy, it was demonstrated that pioglitazone, a PPARγ ligand, increased AKT/mTOR phosphorylation in a dose-dependent manner, leading to better cell viability and inducing increased chondrocyte autophagy (43). However, several works on cancer and neurodegenerative diseases have shown that PPARγ activation inhibits the PI3K/AKT/mTOR signaling pathway (44)(45)(46)(47)(48).…”