AMP-activated protein kinase stimulates osteoblast differentiation and mineralization through autophagy induction

Li, Yang; Su, Jiajia; Sun, Wenchao; Cai, Lin; Deng, Zhouming

doi:10.3892/ijmm.2018.3498

Cited by 53 publications

(58 citation statements)

References 47 publications

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“…Autophagy has been suggested to regulate bone homeostasis by modulating osteoblast differentiation and mineralization, as well as adjusting osteoclast differentiation and function ( 12 , 13 ). Recent studies have reported the cytoprotective effects of autophagy on osteoblast survival, differentiation and mineralization ( 13 – 15 ). However, it is currently unclear whether radiological stress-induced autophagy is actually cytoprotective and which molecular mechanisms are involved.…”

Section: Introductionmentioning

confidence: 99%

Effect of autophagy on irradiation‑induced damage in osteoblast‑like MC3T3‑E1 cells

Yang

et al. 2020

Mol Med Rep

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autophagy is activated under radiation stress, which serves an important role in maintaining bone homeostasis. However, the underlying mechanisms of irradiation-induced autophagy in bone homeostasis is not well understood. The present study aimed to determine the effects of radiation-activated autophagy on pre-osteoblastic Mc3T3-e1 cells. X-ray irradiation activated autophagy in a dose-dependent manner, with an increased fluorescence intensity of monodansylcadaverine staining, increased ratio of microtubule-associated protein 1 light chain 3β (lc3)-ii/lc3-i, decreased p62 expression, and increased aTG5 and beclin-1 expression levels in Mc3T3-e1 cells 72 h after irradiation compared with those in non-irradiated Mc3T3-e1 cells. irradiation reduced colony formation and mineralization in a dose-dependent manner in Mc3T3-e1 cells at 2 and 3 weeks after irradiation, respectively. decreased levels of alkaline phosphatase activity and runt-related transcription factor 2 expression were observed at 72 h post-irradiation. in addition, irradiation-induced apoptosis was accompanied by a decreased ratio of Bcl-2/BaX protein and increased the activity of caspase-3. By contrast, doxycycline (doX)-inhibited autophagy attenuated the decreased colony formation and mineralization, and aggravated the increased cell apoptosis in irradiated Mc3T3-e1 cells. Furthermore, the ratio of phosphorylated P38/P38 was observed to be higher following doX treatment within 1 week of irradiation, which was reversed 2 weeks post-irradiation. in conclusion, doX-inhibited autophagy aggravated X-ray irradiation-induced apoptosis at an early stage, but maintained cell proliferation and mineralization at a late stage in irradiated Mc3T3-e1 cells.

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Section: Introductionmentioning

confidence: 99%

Effect of autophagy on irradiation‑induced damage in osteoblast‑like MC3T3‑E1 cells

Yang

et al. 2020

Mol Med Rep

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“…All of these effects by metformin seem to be related to its action as an The molecular mechanism underlying the role of AMPK activation in osteogenic differentiation and bone regeneration remains unclear. AMPK activation may promote bone formation by enhancing autophagy [42]. AMPK controls the osteogenic differentiation of human MSCs through early mTOR inhibition-mediated autophagy and late activation of the Akt/mTOR signaling axis [43].On the other hand, as a direct substrate of AMPK, RUNX2 can stimulate osteoblast differentiation and bone formation [44].…”

Section: Discussionmentioning

confidence: 99%

Metformin enhances osteogenic differentiation of stem cells from human exfoliated deciduous teeth through AMPK pathway

Zhao

Huang

Pathak

et al. 2020

Preprint

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Stem cells from human exfoliated deciduous teeth (SHEDs) are ideal seed cells in bone tissue engineering. As a first-line anti-diabetic drug, metformin has recently been found to promote bone formation. The purpose of this study was to investigate the effect of metformin on osteogenic differentiation of SHEDs and its underlying mechanism. SHEDs were isolated from the dental pulp of deciduous teeth from healthy children aged from 6 to 12, and their surface antigen markers of stem cells were detected by flow cytometry. The effect of metformin (10 - 200 μM) treatment on SHEDs cell viability, proliferation, and osteogenic differentiation was analyzed. The activation of adenosine 5'-monophosphate-activated protein kinase (AMPK) was determined by western blot assay for the AMPK phosphorylated at Thr172 (p-AMPK). SHEDs were confirmed as mesenchymal stem cells (MSCs) based on the expression of characteristic surface antigens. Metformin (10-200 μM) did not affect the viability and proliferation of SHEDs, but significantly increased the expression of osteogenic genes, the activity of alkaline phosphatase, matrix mineralization, and p-AMPK level in SHEDs. Compound C, a specific inhibitor of AMPK pathway, abolished metformin-induced osteogenic differentiation of SHEDs. Moreover, metformin treatment enhanced pro-angiogenic/osteogenic growth factors BMP2 and VEGF but reduced the osteoclastogenic factor RANKL/OPG expression in SHEDs. In conclusion, metformin could induce the osteogenic differentiation of SHEDs by activating the AMPK pathway and regulates the expression of pro-angiogenic/osteogenic growth factors and osteoclastogenic factors in SHEDs. Therefore, SHEDs, combined with metformin possesses therapeutic potential for bone regeneration and bone defect repair.

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“…(OCN), RUNX2 expression and the induction of mammalian target of rapamycin (mTOR)-mediated autophagy ( Figure 1) (Pantovic et al, 2013;Li et al, 2018a). Furthermore, hormones (e.g., melatonin and ecdysterone), promote osteogenesis by mediating the AMPKα (Thr172)/β-catenin signalling pathway in different osteoblastic cells, which inhibits osteoclast differentiation and function (Xu et al, 2017;Jiang et al, 2019).…”

Section: Figure 1 Model For the Activation Of Ampk During Osteoclast mentioning

confidence: 99%

AMP‐activated protein kinase (AMPK) regulates autophagy, inflammation and immunity and contributes to osteoclast differentiation and functionabs

Tong

Ganta

Liu

2020

Biology of the Cell

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Osteoclasts are multinucleated giant cells, responsible for bone resorption. Osteoclast differentiation and function requires a series of cytokines to remove the old bone, which coordinates with the induction of bone remodelling by osteoblast‐mediated bone formation. Studies have demonstrated that AMP‐activated protein kinase (AMPK) play a negative regulatory role in osteoclast differentiation and function. Research involving AMPK, a nutrient and energy sensor, has primarily focused on osteoclast differentiation and function; thus, its role in autophagy, inflammation and immunity remains poorly understood. Autophagy is a conservative homoeostatic mechanism of eukaryotic cells, and response to osteoclast differentiation and function; however, how it interacts with inflammation remains unclear. Additionally, based on the regulatory function of different AMPK subunits for osteoclast differentiation and function, its activation is regulated by upstream factors to perform bone metabolism. This review summarises the critical role of AMPK‐mediated autophagy, inflammation and immunity by upstream and downstream signalling during receptor activator of nuclear factor kappa‐B ligand‐induced osteoclast differentiation and function. This pathway may provide therapeutic targets for bone‐related diseases, as well as function as a biomarker for bone homoeostasis.

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AMP-activated protein kinase stimulates osteoblast differentiation and mineralization through autophagy induction

Cited by 53 publications

References 47 publications

Effect of autophagy on irradiation‑induced damage in osteoblast‑like MC3T3‑E1 cells

Effect of autophagy on irradiation‑induced damage in osteoblast‑like MC3T3‑E1 cells

Metformin enhances osteogenic differentiation of stem cells from human exfoliated deciduous teeth through AMPK pathway

AMP‐activated protein kinase (AMPK) regulates autophagy, inflammation and immunity and contributes to osteoclast differentiation and functionabs

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