The steady-state expression of connexin43 is maintained by the PI3K/Akt in osteoblasts

Bhattacharjee, Rajib; Kaneda, Makoto; Nakahama, Ken-ichi; Morita, Ikuo

doi:10.1016/j.bbrc.2009.03.044

Cited by 27 publications

(23 citation statements)

References 33 publications

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“…The inhibition of PI3K/Akt signaling results in a decrease in Cx43 mRNA and protein levels in MC3T3E1 cells [39]. We confirmed this reaction with a PI3K inhibitor, LY294002.…”

Section: Discussionsupporting

confidence: 68%

Glucocorticoid Suppresses Connexin 43 Expression by Inhibiting the Akt/mTOR Signaling Pathway in Osteoblasts

et al. 2016

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The inhibition of proliferation or functional alteration of osteoblasts by glucocorticoids (GCs) has been recognized as an important etiology of GC-induced osteoporosis (GIO). Connexin 43 (Cx43) is the most abundant connexin isoform in bone cells and plays important roles in bone remodeling. Despite the important role of Cx43 in bone homeostasis and the prevalence of GIO, the direct action of GCs on Cx43 expression in osteoblasts has been poorly described. The aim of the present study was to evaluate how GCs affect Cx43 expression in osteoblasts. Dexamethasone (Dex) treatment decreased expression of Cx43 RNA and protein in MC3T3-E1 mouse osteoblastic cells. Reduction of Cx43 expression by Dex was dependent on the glucocorticoid receptor (GR), as it was abolished by pretreatment with a GR blocker. Treatment with PTH (1-34), a medication used for GIO management, counteracted the suppression of Cx43 by Dex. Akt or mTOR signaling modulators revealed the involvement of the Akt/mTOR signaling pathway in Dex-induced reduction of Cx43 expression. Moreover, overexpression of Cx43 significantly attenuated Dex-inhibited cell viability and proliferation, as evidenced by MTT and bromodeoxyuridine (BrdU) incorporation assay of MC3T3-E1 cells. To account for possible species or cell type differences, human primary osteoblasts were treated with Dex and similar downregulation of Cx43 by Dex was observed. In addition, immunofluorescent staining for Cx43 further demonstrated an apparent decrease in Dex-treated human osteoblasts, while analysis of lucifer yellow propagation revealed reduced gap junction intercellular communication by Dex. Collectively, these findings indicate that GCs suppress Cx43 expression in osteoblasts via GR and the Akt/mTOR signaling pathway and overexpression of Cx43 may, at least in part, rescue osteoblasts from GC-induced reductions in proliferation.

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“…The inhibition of PI3K/Akt signaling results in a decrease in Cx43 mRNA and protein levels in MC3T3E1 cells [39]. We confirmed this reaction with a PI3K inhibitor, LY294002.…”

Section: Discussionsupporting

confidence: 68%

Glucocorticoid Suppresses Connexin 43 Expression by Inhibiting the Akt/mTOR Signaling Pathway in Osteoblasts

et al. 2016

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“…The PI3K/AKT is an important anti-apoptotic pathway within the cell, and it can induce the formation of IKK by influencing NF-κB and Bcl-2 by phosphorylating GSK-3β, which play a protective role with anti-inflammatory and anti-apoptotic effects (Park et al, 2006;Mullonkal and Toledo-Pereyra, 2007). A previous study showed that PI3K/AKT plays a crucial role in modulating Cx43 expression (Bhattacharjee et al, 2009), conveying mechanical signals to the Cx43 hemichannel and mediating its opening in osteocytes (Batra et al, 2014). Besides, Cx43 has been shown to decrease expression in the heart of AKT1 −/− /iAKT2 knockout mice, revealing that AKT plays an important role in maintaining systolic function and Cx43 protein stability (Ock et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Vinpocetine Protects Against Cerebral Ischemia-Reperfusion Injury by Targeting Astrocytic Connexin43 via the PI3K/AKT Signaling Pathway

et al. 2020

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Vinpocetine (Vinp) is known for its neuroprotective properties. However, the protective mechanism of Vinp against cerebral ischemia/reperfusion (I/R) injury should be further explored. This study was designed to investigate the neuroprotective effects of Vinp against oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro and cerebral I/R injury in vivo and explore whether this mechanism would involve enhancement of astrocytic connexin 43 (Cx43) expression via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In vitro, we detected astrocytic viability and extracellular nitric oxide by an assay kit, intracellular reactive oxygen species by a DCFH-DA probe, inflammation and apoptosis-related protein expression by immunofluorescence staining, and the astrocytic apoptosis rate by flow cytometry. In vivo, we measured the cerebral infarction volume, superoxide dismutase activity, malondialdehyde content, and the expression of inflammation and apoptosis-related proteins. The results indicated that Vinp ameliorated the detrimental outcome of I/R injury. Vinp attenuated astrocytic injury induced by OGD/R and reduced cerebral infarction volume and cerebral edema in rats with cerebral I/R injury. Moreover, Vinp reduced oxidative stress, inflammation, and apoptosis induced by cerebral I/R injury in brain tissues. Meanwhile, Vinp increased p-Cx43 and p-AKT expression, and the p-Cx43/Cx43 and p-AKT/AKT ratio, which was decreased by cerebral I/R injury. Coadministration of PI3K inhibitors LY294002 and BKM120 blunted the effects of Vinp. This study suggests that Vinp protects against cerebral I/R injury via Cx43 phosphorylation by activating the PI3K/AKT pathway.

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“…Lastly, there is communication between osteoblasts and osteocytes via gap junctions [84]. Osteoblasts continuously express connexin 43 at high levels [85]. Furthermore, parathyroid hormone, prostaglandin E 2 , or shear stress, upregulate connexin 43 expression and GJIC activity in osteocytes [8,86,87].…”

Section: Bone Regeneration (Osteoclast-osteoblast Communication)mentioning

confidence: 99%

Cellular communications in bone homeostasis and repair

Nakahama

2010

Cell. Mol. Life Sci.

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124

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Cellular communication between the bone component cells osteoblasts, osteocytes and (pre-)osteoclasts is essential for bone remodeling which maintains bone integrity. As in the remodeling of other organs, cell death is a trigger for remodeling of bone. During the systematic process of bone remodeling, direct or indirect cell-cell communication is indispensable. Thus, osteoblasts induce migration and differentiation of preosteoclasts, which is followed by bone resorption (by mature multinuclear osteoclasts). After completion of bone resorption, apoptosis of mature osteoclasts and differentiation of osteoblasts are initiated. At this time, the osteoblasts do not support osteoclast differentiation but do support bone formation. Finally, osteoblasts differentiate to osteocytes in bone or to bone lining cells on bone surfaces. In this way, old bone areas are regenerated as new bone. In this review the role of cell-cell communication in bone remodeling is discussed.

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The steady-state expression of connexin43 is maintained by the PI3K/Akt in osteoblasts

Cited by 27 publications

References 33 publications

Glucocorticoid Suppresses Connexin 43 Expression by Inhibiting the Akt/mTOR Signaling Pathway in Osteoblasts

Glucocorticoid Suppresses Connexin 43 Expression by Inhibiting the Akt/mTOR Signaling Pathway in Osteoblasts

Vinpocetine Protects Against Cerebral Ischemia-Reperfusion Injury by Targeting Astrocytic Connexin43 via the PI3K/AKT Signaling Pathway

Cellular communications in bone homeostasis and repair

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