The antiviral drug tenofovir, an inhibitor of Pannexin-1-mediated ATP release, prevents liver and skin fibrosis by downregulating adenosine levels in the liver and skin

Feig, Jessica L.; Mediero, Aránzazu; Corciulo, Carmen; Liu, Hailing; Zhang, Jin; Pérez-Aso, Miguel; Picard, Laura; Wilder, Tuere; Cronstein, Bruce N.

doi:10.1371/journal.pone.0188135

Cited by 32 publications

(36 citation statements)

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“…Recently, inhibition of Cx43‐based gap junctions and hemichannels was found to lower the degree of thioacetamide‐triggered liver fibrosis accompanied by superoxide dismutase overactivation and reduced production of inflammatory proteins in mice (Table ) . Using the same mouse model, tenovir, a widely applied antiviral agent, was found to inhibit Panx1‐mediated release of adenosine triphosphate and to counteract liver fibrosis . This complies with a study showing reduced collagen content, hepatic stellate cell activation, inflammation, and regeneration in Panx1 ‐/‐ mice upon repeated treatment with carbon tetrachloride …”

Section: Pathophysiology Of Connexin and Pannexin (Hemi)channelssupporting

confidence: 77%

Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease

et al. 2019

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Connexin proteins are the building blocks of hemichannels, which dock further between adjacent cells to form gap junctions. Gap junctions control the intercellular exchange of critical homeostasis regulators. By doing so, gap junctions control virtually all aspects of the hepatic life cycle. In the last decade, it has become clear that connexin hemichannels also provide a pathway for cellular communication on their own independent of their role as structural precursors of gap junctions, namely between the cytosol of an individual cell and its extracellular environment. In contrast to gap junctions, connexin hemichannels become particularly active in liver disease by facilitating inflammation and cell death. This equally holds true for cellular channels composed of pannexins, being connexin‐like proteins recently identified in the liver that gather in structures reminiscent of hemichannels. This paper gives an overview of the involvement of connexin‐based and pannexin‐based channels in noncancerous liver disease.

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Section: Pathophysiology Of Connexin and Pannexin (Hemi)channelssupporting

confidence: 77%

Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease

et al. 2019

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“…A ). Because we had previously shown that tenofovir treatment diminishes extracellular adenosine levels by inhibiting ATP export via pannexin‐1, we next determined whether increasing extracellular adenosine levels by treatment with dipyridamole reversed the effect of tenofovir on osteoclast formation and found that dipyridamole completely reversed the effect of tenofovir on osteoclast differentiation (IC 50 = 0.3μM; Fig. A ).…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we have found that direct activation of A2AR inhibits NFκB translocation to the nucleus and inhibits osteoclast differentiation by a mechanism that involves cAMP‐PKA‐ERK1/2 signaling, signals downstream of Gnas . Dipyridamole, which does not affect bone homeostasis in A2AR knockout mice, most likely reverses the effect of tenofovir by restoring extracellular adenosine levels that are reduced by tenofovir treatment …”

Section: Discussionmentioning

confidence: 99%

“…We recently demonstrated that tenofovir blocks pannexin‐1‐mediated cellular ATP release leading to diminished extracellular adenosine levels and diminished A2AR‐mediated fibrosis in two murine models . Tenofovir is taken up by cells and converted to tenofovir polyphosphates, which mediate the antiviral effects of the agent.…”

Section: Discussionmentioning

confidence: 99%

“…Dose determination was performed via conversion of animal doses to human equivalent doses based on body surface area …”

Section: Methodsmentioning

confidence: 99%

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Tenofovir Causes Bone Loss via Decreased Bone Formation and Increased Bone Resorption, Which Can Be Counteracted by Dipyridamole in Mice

Conesa-Buendía

Llamas-Granda

Larrañaga-Vera

et al. 2019

Journal of Bone and Mineral Research

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Osteopenia and fragility fractures have been associated with human immunodeficiency virus (HIV) infection. Tenofovir, a common antiviral in HIV treatment, also leads to increases in bone catabolism markers and decreased BMD in children and young adults. In murine models and human cell lines, tenofovir inhibits adenosine triphosphate release and decreases extracellular adenosine levels. Adenosine and adenosine A2A receptor inhibit osteoclast formation, and increase local adenosine concentration with dipyridamole, an agent that blocks adenosine cellular uptake and stimulates new bone formation as well as bone morphogenic protein 2. We hypothesized that tenofovir regulates bone resorption by diminishing endogenous adenosine levels and questioned whether dipyridamole may be a useful treatment to counteract the deleterous bone effects of tenofovir. Primary murine osteoclasts were induced by M‐CSF/RANKL, and the number of TRAP‐positive‐cells was studied after challenge with tenofovir alone or in combination with dipyridamole. Differentiation markers were studied by RT‐PCR and MAPK/NFkB expression by Western blot. Male C57Bl/6 mice were treated as follows: saline 0.9% (control), tenofovir 75 mg/kg/day, dipyridamole 25 mg/kg/day, combination tenofovir/dipyridamole (n = 10, 4 weeks). Calcein/Alizarin Red‐labeling of newly formed bone was used, and long bones were prepared for micro‐computed tomography (μCT)/histology. Tenofovir produced a dose‐dependent increase in osteoclast differentiation (EC50 = 44.5nM) that was reversed by dipyridamole (IC50 = 0.3 μM). Tenofovir increased cathepsin K and NFATc1 mRNA levels and dipyridamole reversed the effect. Dipyridamole reversed the effect of tenofovir on pERK1/2, pp38, and NFkB nuclear translocation. Mice treated with tenofovir lost nearly 10% of their body weight (p < 0.001). μCT revealed decreased BMD and altered trabecular bone in tenofovir‐treated mice, reversed by dipyridamole. TRAP‐staining showed increased osteoclasts in tenofovir‐treated mice (p < 0.005), an effect reversed by dipyridamole. Similar results were obtained for cathepsin K and CD68. RANKL‐positive cells were increased in tenofovir‐treated mice, whereas osteoprotegerin‐positive cells were decreased; both effects were reversed by dipyridamole. These results suggest that treatment with agents that increase local adenosine concentrations, like dipyridamole, might prevent bone loss following tenofovir treatment. © 2019 American Society for Bone and Mineral Research.

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The role of the CD39–CD73–adenosine pathway in liver disease

Wang

Gao

Zhou

et al. 2020

Journal Cellular Physiology

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Extracellular adenosine triphosphate (ATP) is a danger signal released by dying and damaged cells, and it functions as an immunostimulatory signal that promotes inflammation. The ectonucleotidases CD39/ectonucleoside triphosphate diphosphohydrolase-1 and CD73/ecto-5′-nucleotidase are cell-surface enzymes that breakdown extracellular ATP into adenosine. This drives a shift from an ATP-driven proinflammatory environment to an anti-inflammatory milieu induced by adenosine. The CD39-CD73-adenosine pathway changes dynamically with the pathophysiological context in which it is embedded. Accumulating evidence suggests that CD39 and CD73 play important roles in liver disease as critical components of the extracellular adenosinergic pathway. Recent studies have shown that the modification of the CD39-CD73-adenosine pathway alters the liver's response to injury. Moreover, adenosine exerts different effects on the pathophysiology of the liver through different receptors. In this review, we aim to describe the role of the CD39-CD73-adenosine pathway and adenosine receptors in liver disease, highlighting potential therapeutic targets in this pathway, which will facilitate the development of therapeutic strategies for the treatment of liver disease.

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The antiviral drug tenofovir, an inhibitor of Pannexin-1-mediated ATP release, prevents liver and skin fibrosis by downregulating adenosine levels in the liver and skin

Cited by 32 publications

References 60 publications

Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease

Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease

Tenofovir Causes Bone Loss via Decreased Bone Formation and Increased Bone Resorption, Which Can Be Counteracted by Dipyridamole in Mice

The role of the CD39–CD73–adenosine pathway in liver disease

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