Background/Purpose: Osteopenia and fragility fractures have been associated with HIV infection. Tenofovir, a common antiviral in HIV treatment, 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. We have recently reported that Netrin-1 is an autocrine and paracrine regulator of osteoclast differentiation with unique role for Netrin-1 in osteoclast biology and inflammation. We have also described that blosckade of adenoine uotaken with dipyridamole, prevent bone loss caused by tenofovir in mice. We hypothesized that Netrin1 might be involved in bone resorption induced by tenofovir, and if we increase adenosine levels, we could revert the deleterious effect of tenofovir.

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) and after sacrifice, long bones were prepared for histology. Primary murine M-CSF/RANKL-induced were challenge with Tenofovir 1mM alone or in combination with Dipyridamole 1mM, and expression of Netrin-1 and its receptors Unc5B and DCC were study by Western Blot.

Results: Mice treated with tenofovir showed an increased expression of Netrin-1 and its receptor Unc5b when compare to control mice, and treatment with Dipyridamole partially reverting the expression of these molecules. In vitro, tenofovir tenofovir increases Netrin1 expression (44±4% increased vs. basal, p< 0.05) and secretion (16±5% increased vs. basal, p=ns) and Unc5b expression (74±18% increased vs. basal, p< 0.05) 24 hours after stimulation, and pre-treatment with dipyridamole reverted the effect. No changes in DCC expression were observed.

Conclusion: These results suggest that Netrin-1/Unc5b might be involved in bone resorption mediated by tenofovir, and treatment with agents that increase local adenosine concentrations, like Dipyridamole, might prevent this bone loss.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/netrin-1-and-its-receptor-unc5b-mediates-tenofovir-induced-bone-loss-and-dipyridamole-an-agent-that-blocks-adenosine-transporter-is-able-to-modulate-the-signal/