Date: Monday, October 22, 2018
Session Title: Osteoarthritis and Joint Biology – Basic Science Poster I
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Osteopenia and fragility fractures have been associated with HIV infection. Tenofovir, one of the most commonly used antivirals in HIV, also leads to increases in bone catabolism markers and decreased bone mineral density (BMD) in children and young adults. In murine models and human cell lines, Tenofovir inhibits ATP release and decreases extracellular adenosine levels. Adenosine, acting at its adenosine A2A and A2B receptors, inhibits osteoclast formation, and increasing local adenosine concentration with Dipyridamole, an agent that blocks adenosine cellular uptaken, stimulates new bone formation as well as rhBMP-2 by an A2A receptor-dependent effect. We hypothesized that Tenofovir regulates bone resoprtion by diminishing endogenous adenosine levels and determined whether Dipyridamole could counteract the deleterious effects of Tenofovir on bone.
Methods: Male C57Bl/6 mice were treated as follows: IP injection of saline (control), Tenofovir 75mg/Kg/day, Dipyridamole 25mg/Kg/day, combination Tenofovir/Dipyridamole (n=10, 4 weeks). Female C57Bl/6 mice were ovariectomized and treated as follow: sham (no surgery), saline (control), Tenofovir 75mg/Kg/day, Dipyridamole 25mg/Kg/day, combination Tenofovir/Dipyridamole (n=10, 5 weeks). Weekly weight was annotated. DXA scanning was performed before sacrifice. Calcein/AlizarinRed-labelling of newly formed bone was used, and long bones were prepared for microCT/histology.
Male mice treated with Tenofovir lost nearly 10% of body weight (p<0.001). DXA scanning showed a decrease in BMD in mice treated with Tenofovir that was reversed with Dipyridamole. microCT revealed decreased BMD and diminished trabecular bone in Tenofovir-treated mice and reversal by Dipyridamole treatment. 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 OPG-positive-cells decreased, and both effects were reversed by Dipyridamole. In the case of female OVX mice, Tenofovir treatment also produced a decreased in body weight (p<0.05) that was reversed with Dipyridamole. DXA scanning showed decreased BMD in Tenofovir-treated mice and microCT revealed diminished trabecular bone, similar to findings in male mice. Similar results were found for Cathepsin K, CD68, RANKL and OPG-positive-cells.
Conclusion: These results suggest that treatment with agents that increase local adenosine concentrations, like Dipyridamole, might prevent bone loss following Tenofovir treatment.
To cite this abstract in AMA style:Conesa-Buendia FM, Llamas P, Wilder T, Largo R, Herrero-Beaumont G, Cronstein BN, Mediero A. Tenofovir Induces Osteopenia and Dipyridamole, an Inhibitor of the Ent-1 Nucleoside Transporter, Reverses the Osteopenic Effect of Tenofovir In Vivo [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/tenofovir-induces-osteopenia-and-dipyridamole-an-inhibitor-of-the-ent-1-nucleoside-transporter-reverses-the-osteopenic-effect-of-tenofovir-in-vivo/. Accessed June 1, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tenofovir-induces-osteopenia-and-dipyridamole-an-inhibitor-of-the-ent-1-nucleoside-transporter-reverses-the-osteopenic-effect-of-tenofovir-in-vivo/