&lt;p&gt;High Glucose Downregulates Connexin 43 Expression and Its Gap Junction and Hemichannel Function in Osteocyte-like MLO-Y4 Cells Through Activation of the p38MAPK/ERK Signal Pathway&lt;/p&gt;

Yang, Lei; Zhou, Guangping; Li, Mingyang; Li, Yan; Yang, Liqing; Fu, Qin

doi:10.2147/dmso.s239892

Cited by 12 publications

(12 citation statements)

References 49 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%

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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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“…In this study, Cx40 and Cx43 were downregulated in the MS group. The downregulation of Cx in metabolic syndrome was found in not only cardiomyocytes [ 31 ] but also osteocytes [ 34 ]. The downregulation of connexins has also been associated with inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) [ 35 ], which might cause cardiac remodeling and fibrosis, resulting in arrhythmogenicity.…”

Section: Discussionmentioning

confidence: 99%

Characteristics of Ventricular Electrophysiological Substrates in Metabolic Mice Treated with Empagliflozin

Jhuo

Liu

Tasi

et al. 2021

IJMS

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Empagliflozin (EMPA) is a sodium–glucose transporter 2 (SGLT2) inhibitor that functions as a new-generation glucose-lowering agent and has been proven to be beneficial for patients with cardiovascular diseases. However, the possible benefits and mechanisms of its antiarrhythmic effects in cardiac tissue have not yet been reported. In this study, we elucidated the possible antiarrhythmic effects and mechanisms of EMPA treatment in cardiac tissues of metabolic syndrome (MS) mice. A total of 20 C57BL/6J mice (age: 8 weeks) were divided into four groups: (1) control group, mice fed a standard chow for 16 weeks; (2) MS group, mice fed a high-fat diet for 16 weeks; (3) EMPA group, mice fed a high-fat diet for 12 weeks and administered EMPA at 10 mg/kg daily for the following 4 weeks; and (4) glibenclamide (GLI) group, mice fed a high-fat diet for 12 weeks and administered GLI at 0.6 mg/kg daily for the following 4 weeks. All mice were sacrificed after 16 weeks of feeding. The parameters of electrocardiography (ECG), echocardiography, and the effective refractory period (ERP) of the left ventricle were recorded. The histological characteristics of cardiac tissue, including connexin (Cx) expression and fibrotic areas, were also evaluated. Compared with the MS group, the ECG QT interval in the EMPA group was significantly shorter (57.06 ± 3.43 ms vs. 50.00 ± 2.62 ms, p = 0.011). The ERP of the left ventricle was also significantly shorter in the EMPA group than that in the GLI group (20.00 ± 10.00 ms vs. 60.00 ± 10.00 ms, p = 0.001). The expression of Cx40 and Cx43 in ventricular tissue was significantly lower in the MS group than in the control group. However, the downregulation of Cx40 and Cx43 was significantly attenuated in the EMPA group compared with the MS and GLI groups. The fibrotic areas of ventricular tissue were also fewer in the EMPA group than that in the MS group. In this study, the ECG QT interval in the EMPA group was shorter than that in the MS group. Compared with the MS group, the EMPA group exhibited significant attenuation of downregulated connexin expression and significantly fewer fibrotic areas in ventricles. These results may provide evidence of possible antiarrhythmic effects of EMPA.

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“… 16 p38MAPK/ERK signalling has been shown to induce membrane Cx43 internalisation in osteocyte-like MLO-Y4 cells. 46 On the other hand, Cx43 dephosphorylation at serine 282 activates the p38 pathway in cardiomyocytes, 47 and opening of Cx43 hemichannels has been shown to activate p38 MAPK in mouse cortical astrocytes. 48 In future studies, it would be of interest to further investigate the relationship between Cx43 and the MAPK pathway in rPAFs.…”

Section: Discussionmentioning

confidence: 99%

Connexin 43 plays a role in proliferation and migration of pulmonary arterial fibroblasts in response to hypoxia

et al. 2020

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Pulmonary hypertension (PH) is a disease associated with vasoconstriction and remodelling of the pulmonary vasculature. Pulmonary artery fibroblasts (PAFs) play an important role in hypoxic-induced remodelling. Connexin 43 (Cx43) is involved in cellular communication and regulation of the pulmonary vasculature. Using both in vitro and in vivo models of PH, the aims of this study were to (i) investigate the role of Cx43 in hypoxic-induced proliferation and migration of rat PAFs (rPAFs) and rat pulmonary artery smooth muscle cells (rPASMCs) and (ii) determine whether Cx43 expression is dysregulated in the rat sugen5416/hypoxic model of PH. The role of Cx43 in hypoxic-induced proliferation and migration was investigated using Gap27 (a pharmacological inhibitor of Cx43) or genetic knockdown of Cx43 using siRNA. Cx43 protein expression was increased by hypoxia in rPAFs but not rPASMCs. Hypoxic exposure, in the presence of serum, resulted in an increase in proliferation of rPAFs but not rPASMCs. Hypoxic exposure caused migration of rPAFs but not rPASMCs. Phosphorylation of p38 mitogen-activated protein kinase (MAPK) and ERK1/2 were increased by hypoxia in rPAFs. The effects of hypoxia on proliferation, migration and MAPK phosphorylation in rPAFs were attenuated in the presence of Gap27 or Cx43 siRNA. Cx43 protein expression was increased in sugen5416/hypoxic rat lung; this increased expression was not observed in sugen5416/hypoxic rats treated with the MAPK pathway inhibitor GS-444217. In conclusion, Cx43 is involved in the proliferation and migration of rPAFs in response to hypoxia via the MAPK signalling pathway.

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<p>High Glucose Downregulates Connexin 43 Expression and Its Gap Junction and Hemichannel Function in Osteocyte-like MLO-Y4 Cells Through Activation of the p38MAPK/ERK Signal Pathway</p>

Cited by 12 publications

References 49 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

Characteristics of Ventricular Electrophysiological Substrates in Metabolic Mice Treated with Empagliflozin

Connexin 43 plays a role in proliferation and migration of pulmonary arterial fibroblasts in response to hypoxia

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