Melatonin restores the osteoporosis-impaired osteogenic potential of bone marrow mesenchymal stem cells by preserving SIRT1-mediated intracellular antioxidant properties

Chen, Weikai; Chen, Xi; Chen, Angela Carley; Shi, Qin; Pan, Guoqing; Pei, Ming; Yang, Huilin; Liu, Tao; He, Fan

doi:10.1016/j.freeradbiomed.2019.10.412

Cited by 70 publications

(50 citation statements)

References 64 publications

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“…Sirtuin type 1 (SIRT1), a class III histone deacetylase, is closely involved in the regulation of osteogenic differentiation 15,16 . For instance, mechanical stretch induces antioxidant responses and osteogenic differentiation in human mesenchymal stem cells (MSCs) through activation of the AMP‐activated protein kinase‐SIRT1 signaling pathway 17 .…”

Section: Introductionmentioning

confidence: 99%

Resveratrol‐enhanced SIRT1‐mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors

Chen

Gao

et al. 2021

FASEB j.

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Low back pain (LBP) is a major clinical problem that lacks effective treatments. The sensory innervation in porous vertebral endplates and anxiety contributes to spinal hyperalgesia. We hypothesized that SIRT1 activator resveratrol alleviates LBP and anxiety via promotion of osteogenesis in the porous endplates. The hyperalgesia and anxiety‐related behaviors; sensory innervation, inflammation and porosity of endplates; and osteogenic/osteoclastic factors expression were measured following resveratrol treatment after lumbar spine instability (LSI) surgery. To explore whether resveratrol promotes endplates osteogenesis and thus alleviates LBP through activation of SIRT1 in the osteoprogenitor cells of endplates, SIRT1OSX−/− mice were employed. Additionally, the levels of inflammation markers, phosphorylation of cAMP response element‐binding protein (pCREB), and brain‐derived neurotrophic factor (BDNF) in hippocampus were evaluated. After 4 or 8 weeks LSI surgery, the mice suffered from hyperalgesia and anxiety, which were efficiently attenuated by resveratrol at 8 weeks. Resveratrol treatment‐enhanced osteogenesis and decreased endplates porosities accompanied with the reduction of TNFα, IL‐1β, and COX2 levels and CGRP+ nerve fibers innervation in porous endplates. Resveratrol‐mediated endplates osteogenesis, decreased endplates porosities, and analgesic and antianxiety effects were abrogated in SIRT1OSX−/− mice. Furthermore, resveratrol relieved inflammation and increased pCREB and BDNF expression in the hippocampus after 8 weeks, which alleviate anxiety‐related behaviors. This study provides that resveratrol‐mediated porous endplates osteogenesis via the activation of SIRT1 markedly blocked sensory innervation and inflammation in endplates, therefore, alleviating LSI surgery‐induced LBP and hippocampus‐related anxiety.

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Section: Introductionmentioning

confidence: 99%

Resveratrol‐enhanced SIRT1‐mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors

Chen

Gao

et al. 2021

FASEB j.

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“…Correspondingly, our earlier report also revealed that osteogenic differentiation potential of BMSCs was shown to be distinctively higher than that of adipose‐derived MSCs 4 . Besides, BMSCs are the most auspicious and meticulously studied stem cell population; it can be applied to treat numerous bone disorders 8 …”

Section: Introductionmentioning

confidence: 80%

Osteogenic differentiation potential of human bone marrow‐derived mesenchymal stem cells enhanced by bacoside‐A

Ramesh

2020

Cell Biochemistry & Function

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Stem cell therapy is growing rapidly to treat numerous diseases including bone‐associated diseases. Mesenchymal stem cells (MSCs) are most commonly preferred to treat bone diseases because it possesses high osteogenic potency. Though, to obtain maximum osteogenic efficiency of MSCs is challenging. Therefore, this study was planned to evaluate the osteogenic efficiency of human bone marrow derived mesenchymal stem cells (hBMSCs) by bacoside‐A. This study was investigated the activity of alkaline phosphatase (ALP) and expressions of the genes specific to osteogenic regulation mainly runt‐related transcription factor 2 (Runx2), osterix (Osx), osteocalcin (OCN) and collagen type Iα1 (Col I α1) in hBMSCs cultured under osteogenic conditions at different concentrations of bacoside‐A for 14 days. The results of this study depicted significant upregulation in the activity of ALP and expressions of osteogenic regulator genes in bacoside‐A treated cells when compared with control cells. Besides, expressions of glycogen synthase kinase‐3β (GSK‐3β) and Wnt/β‐catenin were evaluated; these expressions were also significantly increased in bacoside‐A treated cells when compared with control cells. This result provides a further supporting evidence of bacoside‐A role on osteogenesis in hBMSCs. The present study suggest that bacoside‐A will be applied to ameliorate the process of osteogenesis in hBMSCs to repair damaged bone structure during MSC‐based therapy; this will be an excellent and auspicious treatment for bone‐associated disorders including osteoporosis. Significance of the study Osteoporosis is a bone metabolic disorder characterized by an imbalance between the activity of osteoblastic bone formation and osteoclastic bone resorption that disrupts the bone microarchitecture. Current anti‐osteoporotic drugs are inhibiting bone resorption, but they are unable to restore the bone structure due to extreme bone remodelling process and causes numerous side effects. The finding of natural bioactive compounds with osteogenic property is very essential for osteoporosis treatment. This study was reported that bacoside‐A ameliorated osteogenic differentiation of hBMSCs through upregulation of osteogenic differentiation genes and Wnt/β‐catenin signalling pathway. This result is indicating that bacoside‐A may be useful for osteoporosis treatments.

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“…Our data showed that melatonin prevented cell death induced by H 2 O 2 damage, decreased the apoptotic index, and improved cell proliferation. In addition, pretreatment with melatonin relieved oxidative stress and restored mitochondrial function, as evidenced by a decrease in ROS production, an increase in the MMP, inhibition of Cyto-C translocation, and upregulation of MnSOD (an antioxidant enzyme essential for cell survival through the catalysis of the spontaneous dismutation of superoxide radicals [59]). Moreover, melatonin activated AMPK and reduced the expression of proteins related to ER stress, such as p-PERK, Bip, p-eIF2α, and DDIT3.…”

Section: Discussionmentioning

confidence: 99%

Melatonin suppresses ER stress-dependent proapoptotic effects via AMPK in bone mesenchymal stem cells during mitochondrial oxidative damage

et al. 2020

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Background Bone marrow mesenchymal stem cells (BMSCs) have been used as important cell-based tools for clinical applications. Oxidative stress-induced apoptosis causes a low survival rate after transplantation, and the underlying mechanisms remain unknown. The endoplasmic reticulum (ER) and mitochondria are vital organelles regulated by adenosine monophosphate (AMP)-activated protein kinase (AMPK), especially during oxidative stress injury. Melatonin exerts an antioxidant effect by scavenging free radicals. Here, we aimed to explore whether cytoprotective melatonin relieves ER stress-mediated mitochondrial dysfunction through AMPK in BMSCs after oxidative stress injury. Methods Mouse BMSCs were isolated and exposed to H2O2 in the absence or presence of melatonin. Thereafter, cell damage, oxidative stress levels, mitochondrial function, AMPK activity, ER stress-related proteins, and apoptotic markers were measured. Additionally, the involvement of AMPK and ER stress in the melatonin-mediated protection of BMSCs against H2O2-induced injury was investigated using pharmacologic agonists and inhibitors. Results Melatonin improved cell survival and restored mitochondrial function. Moreover, melatonin intimately regulated the phosphorylation of AMPK and molecules associated with ER stress pathways. AMPK activation and ER stress inhibition following melatonin administration improved the mitochondrial membrane potential (MMP), reduced mitochondria-initiated oxidative damage, and ultimately suppressed apoptotic signaling pathways in BMSCs. Cotreatment with N-acetyl-l-cysteine (NAC) significantly enhanced the antioxidant effect of melatonin. Importantly, pharmacological AMPK activation/ER stress inhibition promoted melatonin-induced cytoprotection, while pharmacological AMPK inactivation/ER stress induction conferred resistance to the effect of melatonin against H2O2 insult. Conclusions Our data also reveal a new, potentially therapeutic mechanism by which melatonin protects BMSCs from oxidative stress-mediated mitochondrial apoptosis, possibly by regulating the AMPK-ER stress pathway.

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Melatonin restores the osteoporosis-impaired osteogenic potential of bone marrow mesenchymal stem cells by preserving SIRT1-mediated intracellular antioxidant properties

Cited by 70 publications

References 64 publications

Resveratrol‐enhanced SIRT1‐mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors

Resveratrol‐enhanced SIRT1‐mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors

Osteogenic differentiation potential of human bone marrow‐derived mesenchymal stem cells enhanced by bacoside‐A

Melatonin suppresses ER stress-dependent proapoptotic effects via AMPK in bone mesenchymal stem cells during mitochondrial oxidative damage

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