High glucose inhibits osteogenic differentiation and proliferation of MC3T3‑E1 cells by regulating P2X7

Yang, Jinsan; Ma, Chongyang; Zhang, Mao‑Shu

doi:10.3892/mmr.2019.10790

Cited by 10 publications

(10 citation statements)

References 42 publications

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“…This effect was delayed under pre-/diabetic conditions, suggesting towards a delay in osteogenic maturation. This is in line with earlier studies investigating the hyperglycemia and/or hyperinsulinemia on preosteoblasts, osteoblasts or osteocytes [ 11 , 12 , 20 , 21 , 23 ]. Overall, in these studies osteogenic function was reduced under pre-/diabetic conditions.…”

Section: Discussionsupporting

confidence: 92%

“…In the present work, we aimed at developing an in vitro model that can display alterations in bone metabolism characteristic for type 2 diabetes mellitus. In previous studies, the effects of pre-/diabetic conditions have been investigated in mono-cultures with osteogenic cells [ 11 , 12 , 20 , 21 ]. In these models, a decrease in mineralized matrix formation was observed under disease conditions, which does not resemble the in vivo situation where type 2 diabetics are frequently associated with an increased BMD [ 4 , 5 ].…”

Section: Discussionmentioning

confidence: 99%

“…Overall, in these studies osteogenic function was reduced under pre-/diabetic conditions. While in less mature cells induction of proliferation seemed to delay the differentiation process [ 11 , 12 , 21 ], in mature osteocyte-like MLO-Y4 cells a disturbance in cell–cell gap-junctions was proposed as a possible mechanism for the disturbed function [ 20 ]. Interestingly, in 2D coculture presence of hyperglycemia and hyperinsulinemia resulted in increased numbers of THP-1 cells.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

3D Environment Is Required In Vitro to Demonstrate Altered Bone Metabolism Characteristic for Type 2 Diabetics

Häussling

Aspera-Werz

Rinderknecht

et al. 2021

IJMS

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A large British study, with almost 3000 patients, identified diabetes as main risk factor for delayed and nonunion fracture healing, the treatment of which causes large costs for the health system. In the past years, much progress has been made to treat common complications in diabetics. However, there is still a lack of advanced strategies to treat diabetic bone diseases. To develop such therapeutic strategies, mechanisms leading to massive bone alterations in diabetics have to be well understood. We herein describe an in vitro model displaying bone metabolism frequently observed in diabetics. The model is based on osteoblastic SaOS-2 cells, which in direct coculture, stimulate THP-1 cells to form osteoclasts. While in conventional 2D cocultures formation of mineralized matrix is decreased under pre-/diabetic conditions, formation of mineralized matrix is increased in 3D cocultures. Furthermore, we demonstrate a matrix stability of the 3D carrier that is decreased under pre-/diabetic conditions, resembling the in vivo situation in type 2 diabetics. In summary, our results show that a 3D environment is required in this in vitro model to mimic alterations in bone metabolism characteristic for pre-/diabetes. The ability to measure both osteoblast and osteoclast function, and their effect on mineralization and stability of the 3D carrier offers the possibility to use this model also for other purposes, e.g., drug screenings.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

3D Environment Is Required In Vitro to Demonstrate Altered Bone Metabolism Characteristic for Type 2 Diabetics

Häussling

Aspera-Werz

Rinderknecht

et al. 2021

IJMS

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“…The effects of high glucose exposure on BMSCs osteogenesis under differentiating medium were investigated. The results of the present study were consistent with previous finding, demonstrating that high glucose levels affect osteoblast differentiation ( 25 ). The results of the present study demonstrated that high glucose levels inhibited cell proliferation and differentiation, respectively.…”

Section: Discussionsupporting

confidence: 94%

Metformin promotes cell proliferation and osteogenesis under high glucose condition by regulating the ROS‑AKT‑mTOR axis

Zhou

Qiu

et al. 2020

Mol Med Rep

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Metformin, a cost-effective and safe orally administered antidiabetic drug used by millions of patients, has exhibited great interest for its potential osteogenic-promoting properties in different types of cells, including mesenchymal stem cells (MSCs). Diabetic osteopathy is a common comorbidity of diabetes mellitus; however, the underlying molecular mechanisms of metformin on the physiological processes of MSCs, under high glucose condition, remain unknown. To determine the effects of metformin on the regulatory roles of proliferation and differentiation in MSCs, under high glucose conditions, osteogenesis after metformin treatment was detected with Alizarin Red S and ALP staining. The results demonstrated that high glucose levels significantly inhibited cell proliferation and osteogenic differentiation under high glucose conditions. Notably, addition of metformin reversed the inhibitory effects induced by high glucose levels on cell proliferation and osteogenesis. Furthermore, high glucose levels significantly decreased mitochondrial membrane potential (MMP), whereas treatment with metformin helped maintain MMP. Further analysis of mitochondrial function revealed that metformin significantly promoted ATP synthesis, mitochondrial DNA mass and mitochondrial transcriptional activity, which were inhibited by high glucose culture. Furthermore, metformin significantly scavenged reactive oxygen species (ROS) induced by high glucose levels, and regulated the ROS-AKT-mTOR axis inhibited by high glucose levels, suggesting the protective effects of metformin against high glucose levels via regulation of the ROS-AKT-mTOR axis. Taken together, the results of the present study demonstrated the protective role of metformin on the physiological processes of MSCs, under high glucose condition and highlighted the potential molecular mechanism underlying the effect of metformin in promoting cell proliferation and osteogenesis under high glucose condition.

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“…Association between P2X7, proliferation and survival has been demonstrated in several primary cell types including osteoblasts (Grol et al, 2013;Agrawal et al, 2017;Yang et al, 2019), microglia (Monif et al, 2009), and CD8 + memory T cells (Borges da Silva et al, 2018) where it supports physiological functions such as inflammatory responses and osteogenesis. However, increased P2X7 activity was also linked with increased proliferation and survival in many cancer cell types including pancreatic cancer (Giannuzzo et al, 2016), leukemia (Salaro et al, 2016) and glioma (Ji et al, 2018).…”

Section: Proliferationmentioning

confidence: 99%

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

et al. 2020

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P2X7 is a transmembrane receptor expressed in multiple cell types including neurons, dendritic cells, macrophages, monocytes, B and T cells where it can drive a wide range of physiological responses from pain transduction to immune response. Upon activation by its main ligand, extracellular ATP, P2X7 can form a nonselective channel for cations to enter the cell. Prolonged activation of P2X7, via high levels of extracellular ATP over an extended time period can lead to the formation of a macropore, leading to depolarization of the plasma membrane and ultimately to cell death. Thus, dependent on its activation state, P2X7 can either drive cell survival and proliferation, or induce cell death. In cancer, P2X7 has been shown to have a broad range of functions, including playing key roles in the development and spread of tumor cells. It is therefore unsurprising that P2X7 has been reported to be upregulated in several malignancies. Critically, ATP is present at high extracellular concentrations in the tumor microenvironment (TME) compared to levels observed in normal tissues. These high levels of ATP should present a survival challenge for cancer cells, potentially leading to constitutive receptor activation, prolonged macropore formation and ultimately to cell death. Therefore, to deliver the proven advantages for P2X7 in driving tumor survival and metastatic potential, the P2X7 macropore must be tightly controlled while retaining other functions. Studies have shown that commonly expressed P2X7 splice variants, distinct SNPs and posttranslational receptor modifications can impair the capacity of P2X7 to open the macropore. These receptor modifications and potentially others may ultimately protect cancer cells from the negative consequences associated with constitutive activation of P2X7. Significantly, the effects of both P2X7 agonists and antagonists in preclinical tumor models of cancer demonstrate the potential for agents modifying P2X7 function, to provide innovative cancer therapies. This review summarizes recent advances in understanding of the structure and functions of P2X7 and how these impact P2X7 roles in cancer progression. We also review potential therapeutic approaches directed against P2X7.

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High glucose inhibits osteogenic differentiation and proliferation of MC3T3‑E1 cells by regulating P2X7

Cited by 10 publications

References 42 publications

3D Environment Is Required In Vitro to Demonstrate Altered Bone Metabolism Characteristic for Type 2 Diabetics

3D Environment Is Required In Vitro to Demonstrate Altered Bone Metabolism Characteristic for Type 2 Diabetics

Metformin promotes cell proliferation and osteogenesis under high glucose condition by regulating the ROS‑AKT‑mTOR axis

P2X7 in Cancer: From Molecular Mechanisms to Therapeutics

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