Advanced Glycation End Products Affect Osteoblast Proliferation and Function by Modulating Autophagy Via the Receptor of Advanced Glycation End Products/Raf Protein/Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase/Extracellular Signal-regulated Kinase (RAGE/Raf/MEK/ERK) Pathway

Meng, Hong‐Zheng; Zhang, Weilin; Liu, Fei; Yang, Mon-Yuan

doi:10.1074/jbc.m115.669499

Cited by 63 publications

(47 citation statements)

References 47 publications

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“…Reductions in enzymatic collagen crosslinking have also been reported by others [16,17]. High levels of advanced glycation end (AGE) products are likely to be implicated as they have detrimental effects on the bone matrix by increasing collagen stiffness and also modifying osteoblast activity [18][19][20], which might contribute to the low bone turnover observed in T2DM [4].…”

Section: Introductionmentioning

confidence: 70%

High fat-fed diabetic mice present with profound alterations of the osteocyte network

Mabilleau

Perrot

Flatt

et al. 2016

Bone

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Diabetes mellitus is considered to be an independent risk factor for bone fragility fractures. Reductions in bone mass, observed only with type 1 diabetes mellitus, as well as modifications of bone microarchitectures and tissue material properties are landmarks of diabetes-related bone alterations. An interesting feature observed in type 2 diabetes mellitus (T2DM) is the augmented concentration in circulating sclerostin. This observation prompts us to hypothesize that modifications of osteocyte network and perilacunar mineralization occur in T2DM. As such, the aims of the present study were to ascertain by quantitative backscattered electron imaging, confocal microscopy and image analysis, modifications of perilacunar tissue mineral density, osteocyte morphology and osteocyte network topology in a mouse model of high fat-induced type 2 diabetes. As compared with lean control animals, diabetic mice exhibited a significant 48% decrease in perilacunar mineralization heterogeneity although mean perilacunar mineralization was unchanged. Furthermore, in diabetic animals, osteocyte volume was significantly augmented by 34% with no change in the overall number of dendrite processes. Finally, the network topology was profoundly modified in diabetic mice with increases in the mean node degree, mean node volume and hub numbers whilst the mean link length was reduced. Overall, it appeared that in diabetic animals, the dendritic network exhibited features of a scale-free network as opposed to the single-scale characteristic observed in lean controls. However, it is important to ascertain whether diabetic patients exhibit such modifications of the osteocyte network and whether anti-diabetic drugs could restore normal osteocyte and network parameters, thereby improving bone quality and protecting against fragility fractures.

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Section: Introductionmentioning

confidence: 70%

High fat-fed diabetic mice present with profound alterations of the osteocyte network

Mabilleau

Perrot

Flatt

et al. 2016

Bone

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“…40, 41 However, the effect of AGEs on autophagy in mesangial cells is unknown. Because it is difficult to monitor autophagy, 21 we have conducted a series of experiments to examine autophagy-related markers in AGE-treated mesangial cells, including LC3 conversion, autophagic vesicle formation and the increase/decrease in expression of several autophagy-related proteins (Beclin-1/p62).…”

Section: Discussionmentioning

confidence: 99%

“…28, 29, 41 However, little is known about the function of autophagy in mesangial cells under stress conditions. Although increased ROS production triggered autophagy in AGE-treated cells, we observed increased intracellular ROS and mitochondrial ROS generation in mesanigal cells, accompanied by increased autophagic clearance.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of autophagy increased AGE/ROS-mediated apoptosis in mesangial cells

Fan

Wang

et al. 2016

Cell Death Dis

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The aim of our study was to investigate the role of autophagy, a homeostatic process involved in the lysosomal degradation of damaged cell organelles and proteins, in regulating the survival of mesangial cells treated with advanced glycation end products (AGEs). In the present study, AGEs induced mitochondrial depolarization and led to mitochondrial-dependent apoptosis in mesangial cells, as shown by the loss of the mitochondrial membrane potential; increased Bax processing; increased Caspase-9, Caspase-3 and PARP cleavage; and decreased Bcl-2 expression. Meanwhile, AGEs also triggered autophagy flux in mesangial cells, as confirmed by the presence of autophagic vesicles, the conversion of LC3II/LC3I and the increase/decrease in Beclin-1/p62 expression. Interestingly, this study reported apparent apoptosis and autophagy that were dependent on reactive oxygen species (ROS) production. Scavenging ROS with N-acetyl-l-cysteine could prevent the appearance of the autophagic features and reverse AGE-induced apoptosis. Moreover, AGE-triggered mitophagy, which was confirmed by the colocalization of autophagosomes and mitochondria and Parkin translocation to mitochondria, played a potential role in reducing ROS production in mesangial cells. Additionally, inhibition of autophagy significantly enhanced AGE-induced cell apoptosis. Taken together, our data suggest that ROS were the mediators of AGE-induced mesangial cell apoptosis and that autophagy was likely to be the mechanism that was triggered to repair the ROS-induced damage in the AGE-treated cells and thereby promote cell survival. This study provides new insights into the molecular mechanism of autophagy involved in AGE-induced apoptosis in mesangial cells.

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“…Other studies have indicated that autophagy contributes to primary osteoporosis [11]. In previous work, our group identified autophagy as a potential therapeutic target in type 2 diabetic osteoporosis [12]. Although many articles have reported a relationship between melatonin and autophagy, the specific mechanism whereby melatonin regulates autophagy remains controversial [13, 14], and has not been described for type 2 diabetic osteoporosis.…”

Section: Introductionmentioning

confidence: 99%

Melatonin suppresses autophagy in type 2 diabetic osteoporosis

et al. 2016

Self Cite

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Type 2 diabetes mellitus is often complicated by osteoporosis, a process which may involve osteoblast autophagy. As melatonin suppresses autophagy under certain conditions, we its investigated the effects on bone autophagy during diabetes. We first assessed different body parameters in a diabetic rat model treated with various concentrations of melatonin. Dynamic biomechanicalmeasurements, bone organization hard slice dyeing and micro-CT were used to observe the rat bone microstructure, and immunohistochemistry was used to determine levels of autophagy biomarkers. We also performed in vitro experiments on human fetal osteoblastic (hFOB1.19) cells cultured with high glucose, different concentrations of melatonin, and ERK pathway inhibitors. And we used Western blotting and immunofluorescence to measure the extent of osteogenesis and autophagy. We found that melatonin improved the bone microstructure in our rat diabetes model and reduced the level of autophagy(50 mg/kg was better than 100 mg/kg). Melatonin also enhanced osteogenesis and suppressed autophagy in osteoblasts cultured at high glucose levels (10 μM was better than 1 mM). This suggests melatonin may reduce the level of autophagy in osteoblasts and delay diabetes-induced osteoporosis by inhibiting the ERK signaling pathway.

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Cited by 63 publications

References 47 publications

High fat-fed diabetic mice present with profound alterations of the osteocyte network

High fat-fed diabetic mice present with profound alterations of the osteocyte network

Inhibition of autophagy increased AGE/ROS-mediated apoptosis in mesangial cells

Melatonin suppresses autophagy in type 2 diabetic osteoporosis

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