Autophagy plays a protective role in cell death of osteoblasts exposure to lead chloride

Lv, Xiaohua; Zhao, Dahang; Cai, Shi-Zhong; Luo, Sheng; You, Tianyan; Xu, Bin; Chen, Ke

doi:10.1016/j.toxlet.2015.09.014

Cited by 44 publications

(26 citation statements)

References 42 publications

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“…The effect of Zoledronate on the viability or apoptosis of HUVECs was investigated, due to the intricate crosstalk between autophagy and apoptosis (24). Zoledronate was demonstrated to significantly decrease the viability of HUVECs in a dose-dependent manner compared with untreated control (P<0.01), as demonstrated in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, the ability of Zoledronate to induce autophagy in endothelial cells remains unknown. In addition, autophagy has been suggested to be involved in crosstalk with apoptosis by inhibiting or promoting the process (21,24). Thus, the present study hypothesized that Zoledronate may induce apoptosis in human umbilical vein endothelial cells (HUVECs), partially, by affecting autophagy.…”

Section: Introductionmentioning

confidence: 99%

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Zoledronate induces autophagic cell death in human umbilical vein endothelial cells via Beclin-1 dependent pathway activation

Wang

Han

et al. 2016

Molecular Medicine Reports

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Zoledronate has been reported to exhibit pro-apoptotic and anti-angiogenic effects in endothelial cells, which partially contributes to bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ). Zoledronate can also induce autophagic cell death. The present study hypothesized that Zoledronate may activate autophagy to exert pro-apoptotic effects in endothelial cells and aimed to investigate the effect of Zoledronate on human umbilical vein endothelial cells (HUVECs) and explore the underlying mechanisms. The current study demonstrated that Zoledronate induced autophagy in HUVECs in a dose-dependent manner, as demonstrated by increased levels of microtubule-associated proteins 1A/1B light chain 3B-II (LC3B-II) and Beclin-1, and decreased levels of sequestome 1 (SQSTM1). In addition, treatment with chloroquine further increased LC3B-II and increased SQSTM1 levels, indicating that Zoledronate induces autophagy by increasing autophagic activity. Flow cytometry and Hoechst 33258 staining revealed that inhibition of autophagy with 3-methyladenine markedly attenuated Zoledronate-induced apoptosis. Furthermore, genetic knockdown of Beclin-1 significantly inhibited autophagy and apoptosis induced by Zoledronate. The present study therefore demonstrated that Zoledronate may promote Beclin-1-mediated autophagy to induce endothelial cell apoptosis, and suggests that blocking autophagy may represent a novel approach for the prevention of BP-ONJ in patients receiving Zoledronate.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Zoledronate induces autophagic cell death in human umbilical vein endothelial cells via Beclin-1 dependent pathway activation

Wang

Han

et al. 2016

Molecular Medicine Reports

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“…5 Previous studies have demonstrated that basal autophagy is vital for normal proximal tubule function, and genetic or pharmacologic blockade of autophagy strongly enhanced acute kidney injury induced by cisplatin or ischemia-reperfusion. 6, 7, 8, 9 Moreover, report by Lv et al 10 and Sui et al 11 showed that Pb promoted the autophagy in cultured osteoblasts and cardiofibroblasts, respectively. By contrast, our research group has recently found that 0.5 μ M Pb treatment for 12 h blocked the autophagic flux in rPT cells, 12 while the underlying molecular mechanism of impaired autophagic flux during Pb exposure remains to be elucidated.…”

mentioning

confidence: 97%

Autophagy blockade and lysosomal membrane permeabilization contribute to lead-induced nephrotoxicity in primary rat proximal tubular cells

et al. 2017

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Lead (Pb) is a known nephrotoxicant that causes damage to proximal tubular cells. Autophagy has an important protective role in various renal injuries, but the role of autophagy in Pb-elicited nephrotoxicity remains largely unknown. In this study, Pb promoted the accumulation of autophagosomes in primary rat proximal tubular (rPT) cells, and subsequent findings revealed that this autophagosome accumulation was caused by the inhibition of autophagic flux. Moreover, Pb exposure did not affect the autophagosome–lysosome fusion in rPT cells. Next, we found that Pb caused lysosomal alkalinization, may be through suppression of two V-ATPase subunits. Simultaneously, Pb inhibited lysosomal degradation capacity by affecting the maturation of cathepsin B (CTSB) and cathepsin D (CTSD). Furthermore, translocation of CTSB and CTSD from lysosome to cytoplasm was observed in this study, suggesting that lysosomal membrane permeabilization (LMP) occurred in Pb-exposed rPT cells. Meanwhile, Pb-induced caspase-3 activation and apoptosis were significantly but not completely inhibited by CTSB inhibitor (CA 074) and CTSD inhibitor (pepstatin A), respectively, demonstrating that LMP-induced lysosomal enzyme release was involved in Pb-induced apoptosis in rPT cells. In conclusion, Pb-mediated autophagy blockade in rPT cells is attributed to the impairment of lysosomal function. Both inhibition of autophagic flux and LMP-mediated apoptosis contribute to Pb-induced nephrotoxicity in rPT cells.

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“…The dysregulation of autophagy is known to be involved in various diseases, including tumorigenesis, disease of the immune system, heart disease and vascular disease (19)(20)(21)(22). Previous studies have demonstrated that autophagy has a protective effect in the death of osteoblasts following exposure to lead chloride (23) and that impairment in autophagy aggravates the inhibitory effects of high glucose on osteoblast viability and function (24). However, the role of autophagy on dioscin-induced osteoblastic cell proliferation and differentiation remains to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Dioscin enhances osteoblastic cell differentiation and proliferation by inhibiting cell autophagy via the ASPP2/NF-κβ pathway

Zhu

Bao

Chen

et al. 2017

Molecular Medicine Reports

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Dioscin, a typical steroid saponin, has been reported to promote osteoblastic cell differentiation. However, the underling mechanisms remain to be elucidated. In the present study, it was identified that dioscin (0.5, 1, 5, 10 and 25 µg/ml) promoted MC3T3‑E1 cell proliferation and differentiation in a dose‑dependent manner. Western blot analysis showed that dioscin regulated autophagy‑associated protein expression in MC3T3‑E1 cells; it promoted the expression of apoptosis stimulated protein of p53‑2 (ASPP2), and inhibited the expression of nuclear factor (NF)‑κβ and microtubule‑associated protein 1 light chain 3β, in a concentration‑dependent manner. Caffeic acid phenethyl ester (CAPE) was used to inhibit the activation of NF‑κB and examine the effect of the ASPP2/NF‑κβ pathway on osteoblastic cell differentiation, proliferation and autophagy. It was identified that CAPE reversed the regulation of dioscin on osteoblastic cell differentiation, proliferation and autophagy. In conclusion, the present study revealed that dioscin promoted osteoblast proliferation and differentiation by inhibiting cell autophagy via the ASPP2/NF‑κβ pathway. These results are the first, to the best of our knowledge, to reveal the involvement of autophagy in the effects of dioscin on the prevention and therapy of osteoporosis.

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Autophagy plays a protective role in cell death of osteoblasts exposure to lead chloride

Cited by 44 publications

References 42 publications

Zoledronate induces autophagic cell death in human umbilical vein endothelial cells via Beclin-1 dependent pathway activation

Zoledronate induces autophagic cell death in human umbilical vein endothelial cells via Beclin-1 dependent pathway activation

Autophagy blockade and lysosomal membrane permeabilization contribute to lead-induced nephrotoxicity in primary rat proximal tubular cells

Dioscin enhances osteoblastic cell differentiation and proliferation by inhibiting cell autophagy via the ASPP2/NF-κβ pathway

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