Pioglitazone inhibits advanced glycation end product-induced matrix metalloproteinases and apoptosis by suppressing the activation of MAPK and NF-κB

Zhang, Haibin; Zhou, Ying; Chen, Cheng; Li, Yuqing; Ma, Chi; Wang, Zhaojun

doi:10.1007/s10495-016-1280-z

Cited by 49 publications

(56 citation statements)

References 36 publications

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“…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.…”

Section: Discussionmentioning

confidence: 89%

“…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, ). However, little information is known about AGEs effect on the autophagic activity of human chondrocytes or promotion of chondrocytes.…”

Section: Introductionmentioning

confidence: 99%

“…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, ).…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Zhang

Chen

et al. 2018

Cell Biology International

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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.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wang

Zhang

Chen

et al. 2018

Cell Biology International

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“…Increasing studies report the critical role of BRD4 in the regulation of inflammatory response, suggesting that BRD4 might be implicated in the pathology of diabetes (35,36). In addition, MMPs, as a marker of degeneration in IVDs, are significantly enhanced in different stresses (13,37). Moreover, MMP-13 is more potent than other ECM catabolic enzymes at cleaving a broad substrate such as type II collagen and aggrecan (10).…”

Section: Disscusionmentioning

confidence: 99%

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

Wang

Chen³

et al. 2019

FASEB j.

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Diabetes mellitus may lead to intervertebral disc degeneration (IVDD). Matrix metalloproteinase‐13 (MMP‐13) is one of the major catabolic factors in extracellular matrix (ECM) metabolism of nucleus pulposus cells (NPCs) and contributes to diabetic IVDD. Bromodomain‐containing protein 4 (BRD4) is a member of the bromodomain and extraterminal protein family and is implicated in chronic inflammation. Here, we report that the expression of BRD4 and MMP‐13 was elevated in diabetic nucleus pulposus tissues as well as in advanced glycation end products (AGEs)‐treated NPCs; also, the regulatory effect of BRD4 on MMP‐13 was studied. We found that MMP‐13 was regulated by MAPK and NF‐κB signaling as well as autophagy in AGEs‐treated NPCs. Next, we explored the role of BRD4 in regulation of MAPK, NF‐κB signaling, and autophagy. The results showed that BRD4 is the upstream regulator of all of these 3 factors, and inhibition of BRD4 may suppress MAPK and NF‐κB signaling while activating autophagy in AGEs‐treated NPCs. Finally, we demonstrated that BRD4 inhibition may suppress MMP‐13 expression in diabetic NPCs in vitro as well as in vivo; meanwhile, it may preserve ECM in diabetic rats. Our study demonstrates that inhibition of BRD4 may suppress MAPK and NF‐κB signaling and activate autophagy to suppress MMP‐13 expression in diabetic IVDD, and diabetic IVDD may be compromised by BRD4 inhibitors.—Wang, J., Hu, J., Chen, X., Huang, C., Lin, J., Shao, Z., Gu, M., Wu, Y., Tian, N., Gao, W., Zhou, Y., Wang, X., Zhang, X. BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration. FASEB J. 33, 11555–11566 (2019). http://www.fasebj.org

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“…Increasing evidence indicates an elevation in cytoplasmic Ca 2+ levels activates the mitogen-activated protein kinase (MAPK) cascade. Three distinct groups of MAPKs, including extracellular signal-regulated protein kinase 1/2 (Erk1/2), c-Jun N-terminal kinase (JNK), and p38 MAPK, are also involved in chondrocyte apoptosis and cartilage degeneration in a rat osteoarthritis model [9][10][11].…”

Section: +mentioning

confidence: 99%

The Transient Receptor Potential Channel, Vanilloid 5, Induces Chondrocyte Apoptosis via Ca2+ CaMKII–Dependent MAPK and Akt/ mTOR Pathways in a Rat Osteoarthritis Model

Wei

Jin

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Chondrocyte apoptosis is a central pathological feature of cartilage in osteoarthritis (OA). Accumulating evidence suggests that calcium ions (Ca²⁺) are an important regulator of apoptosis. Previously, we reported that the transient receptor potential channel vanilloid (TRPV5) is upregulated in monoiodoacetic acid (MIA)-induced OA articular cartilage. Methods: The protein levels of TRPV5, phosphorylated Ca²⁺/calmodulin-dependent kinase II (p-CaMKII), and total CaMKII were detected in vivo using western blotting techniques. Primary chondrocytes were isolated and cultured in vitro. Then, p-CAMKII was immunolocalized by immunofluorescence in chondrocytes. Fluo-4AM staining was used to assess intracellular Ca²⁺. Annexin V-fluorescein isothiocyanate / propidium iodide flow cytometric analysis was performed to determine chondrocyte apoptosis. Western blotting techniques were used to measure the expression of apoptosis-related proteins. Results: We found that ruthenium red (aTRPV5inhibitor)or(1-[N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperaze (KN-62) (an inhibitor of Ca^2+/calmodulin-dependent kinase II (CaMKII) phosphorylation) can relieve or even reverse OA in vivo. We found that TRPV5 has a specific role in mediating extracellular Ca²⁺ influx leading to chondrocyte apoptosis in vitro. The apoptotic effect in chondrocytes was inhibited by KN-62. We found that activated p-CaMKII could elicit the phosphorylation of extracellular signal-regulated protein kinase 1/2, c-Jun N-terminal kinase, and p38, three important regulators of the mitogen-activated protein kinase (MAPK) cascade. Moreover, we also showed that activated p-CaMKII could elicit the phosphorylation of protein kinase B (Akt) and two important downstream regulators of mammalian target of rapamycin (mTOR): 4E-binding protein, and S61 kinase. Conclusion: Our results demonstrate that upregulated TRPV5 may be an important initiating factor that activates CaMKII phosphorylation via the mediation of Ca²⁺ influx. In turn, activated p-CaMKII plays a critical role in chondrocyte apoptosis via MAPK and Akt/mTOR pathways.

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Pioglitazone inhibits advanced glycation end product-induced matrix metalloproteinases and apoptosis by suppressing the activation of MAPK and NF-κB

Cited by 49 publications

References 36 publications

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

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

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

The Transient Receptor Potential Channel, Vanilloid 5, Induces Chondrocyte Apoptosis via Ca2+ CaMKII–Dependent MAPK and Akt/ mTOR Pathways in a Rat Osteoarthritis Model

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