Translating connexin biology into therapeutics

Becker, David L.; Phillips, Anthony R.J.; Duft, Bradford J.; Kim, Yeri; Green, Colin

doi:10.1016/j.semcdb.2015.12.009

Cited by 35 publications

(28 citation statements)

References 84 publications

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“…Currently, Cx43 expression levels and functions have been presented in skin injury, skeletal muscle regeneration (82), ischemia/reperfusion injury (83) and cornea repair (84). The Cx-associated compounds are in development and indicate promising therapeutic opportunities in preclinical evaluation (85). Non-toxic Cx43 specific inhibitors may also be effective for the treatment of wounds, skin cancer or other skin associated disorders.…”

Section: Resultsmentioning

confidence: 99%

Connexin 43: Key roles in the skin

Zhang

Cui

2017

Biomedical Reports

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Abstract. Gap junctions are tightly packed intercellular channels that serve a common purpose of allowing the intercellular exchange of small metabolites, second messengers and electrical signals. Connexins (Cxs) are gap junction proteins. Currently, 20 and 21 members of Cxs have been characterized in mice and humans, respectively. Connexin 43 (Cx43) is the most ubiquitously expressed type of Cx in the skin. It is produced by various different types of skin cell, such as keratinocytes, fibroblasts, endothelial and basal cells, melanocytes and dermal papilla cells. At present, more evidence indicates that Cx43 has an important role in skin repair and skin tumor development, as well as in skin cell invasion and metastasis. In this review, current knowledge regarding the regulation and function of Cx43 is summarized and the therapeutic potential of regulating Cx43 activity is discussed.

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Section: Resultsmentioning

confidence: 99%

Connexin 43: Key roles in the skin

Zhang

Cui

2017

Biomedical Reports

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“…The results reported here demonstrate that the CTD of Cx43 protein plays pivotal roles in normal chondrocyte function and cartilage structure. Some compounds such as Cx mimetic peptides with conserved homology to the cytoplasmic domains of Cx43 are being considered as candidates to improve the rate of wound repair in connective tissues [70–74]. The potential therapeutic implications of novel tissue repair compounds that modulates the CTD of Cx43 protein is an exciting and promising field for degenerative diseases such as osteoarthritis and other cartilage and bone disorders such as osteoporosis.…”

Section: Discussionmentioning

confidence: 99%

The C-terminal domain of connexin43 modulates cartilage structure via chondrocyte phenotypic changes

et al. 2016

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Chondrocytes in cartilage and bone cells population express connexin43 (Cx43) and gap junction intercellular communication (GJIC) is essential to synchronize cells for coordinated electrical, mechanical, metabolic and chemical communication in both tissues. Reduced Cx43 connectivity decreases chondrocyte differentiation and defective Cx43 causes skeletal defects. The carboxy terminal domain (CTD) of Cx43 is located in the cytoplasmic side and is key for protein functions. Here we demonstrated that chondrocytes from the CTD-deficient mice, K258stop/Cx43KO and K258stop/K258stop, have reduced GJIC, increased rates of proliferation and reduced expression of collagen type II and proteoglycans. We observed that CTD-truncated mice were significantly smaller in size. Together these results demonstrated that the deletion of the CTD negatively impacts cartilage structure and normal chondrocyte phenotype. These findings suggest that the proteolytic cleavage of the CTD under pathological conditions, such as under the activation of metalloproteinases during tissue injury or inflammation, may account for the deleterious effects of Cx43 in cartilage and bone disorders such as osteoarthritis.

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“…Some studies have shown that GJIC regulation by Cx43 is related to pro-apoptotic and anti-apoptotic activities [11]. Additionally, Cx43 is thought to be activated by a half channel, rather than GJIC, functioning to protect cells from oxidative stress, metabolic inhibition, and other cellular damage [12–14]. Thus, although our results provide important insights into these pathways, the roles of Cx43 in U251 proliferation, migration, and apoptosis require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Effects of Connexin43 Overexpression on U251 Cell Growth, Migration, and Apoptosis

Yu²,

Zhang

et al. 2017

Med Sci Monit

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BackgroundGlioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor with a high incidence in adults. Connexin43 (Cx43) has general roles in tumorigenesis and is expressed in U251 glioma cells. Accordingly, the effects of Cx43 on the growth, migration, and apoptosis and the underlying mechanisms mediating Cx43-dependent migration and apoptosis were examined in U251 cells.Material/MethodsA Cx43-overexpressing U251 cell line was generated to analyze the effects of Cx43 overexpression on cell growth, wound healing, and apoptosis-related protein expression after treatment with temozolomide.ResultsThe growth rate of U251 cells overexpressing Cx43 was significantly lower than that of parental wild-type cells, and cell morphology was considerably altered. The expression level of Bcl-2 was higher and the expression levels of Bax and caspase-3 were lower in cells overexpressing Cx43 than in wild-type cells. Additionally, the Bax/Bcl-2 ratio decreased.ConclusionsCx43 inhibited the growth of U251 cells, promoted morphological changes and migration, and inhibited apoptosis via a mitochondria-associated pathway.

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Translating connexin biology into therapeutics

Cited by 35 publications

References 84 publications

Connexin 43: Key roles in the skin

Connexin 43: Key roles in the skin

The C-terminal domain of connexin43 modulates cartilage structure via chondrocyte phenotypic changes

Effects of Connexin43 Overexpression on U251 Cell Growth, Migration, and Apoptosis

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