Abstract
Semaphorin 4D (Sema4D) is a neurotrophin that is secreted by osteoclasts and binds to its receptor PlexinB1 on osteoblasts to inhibit their differentiation and function. Adenosine A2A activation inhibits osteoclast Sema4D-mediated secretion, diminishes inflammatory osteolysis and prevents bone loss following tenofovir (one of the most used antivirals in HIV). Therefore, tenofovir might activate Sema4D signaling to alter bone turnover. Female C57Bl/6/A2AKO mice were ovariectomized and treated with saline (control), tenofovir 75 mg/Kg/day, dipyridamole 25 mg/Kg/day or a combination for 5 weeks and long bones were prepared for histology. Primary murine-induced osteoclast/osteoblast were challenged with tenofovir/dipyridamole 1 μM each, and the expression of Sema4D/PlexinB1, RhoA/ROCK/IGF1R was studied by RT-PCR, Western blot and immunostaining. In vivo tenofovir showed an increased expression of Sema4D when compared to control mice, and dipyridamole reverted the expression in an A2A-dependent manner. In vitro, tenofovir increases Sema4D expression and secretion in osteoclast precursors, and pre-treatment with dipyridamole reverted this effect. pRhoA and ROCK1 activation were increased and IRS1/IGF1R expression was diminished by tenofovir in the Vav3/ARHGAP18 mechanism in osteoblast precursors and reverted by dipyridamole in an A2A-dependent manner. This suggests that tenofovir increases bone loss by activation of Sema4D/PlexinB1 signaling, which inhibits osteoblast differentiation. Agents that increase local adenosine concentrations, such as dipyridamole, might prevent bone loss following the inhibition of this pathway.
Highlights
Semaphorin 4D (Sema4D)/CD100 is secreted by osteoclasts in the presence of RANKL and binds to its receptor PlexinB1 on osteoblasts to inhibit their differentiation and function by activating RhoA/ROCK, which inhibits insulin-like growth factor-1 (IGF-1)
Immunity, and knowing that tenofovir diminished bone mineral density (BMD) in HIV patients, we, hypothesize that Sema4D signaling might be activated under tenofovir treatment, and increasing extracellular adenosine concentration with dipyridamole may counteract this effect by the activation of adenosine A2A receptor
Mice Treated with Tenofovir Showed an Increased Expression of Sema4D
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. We have recently demonstrated that tenofovir, via a decrease in extracellular ATP and adenosine levels, increases osteoclast differentiation and function both in vitro and in vivo, reduces bone production and bone volume, and inhibits bone formation in vivo [22]. We observed that treatment with agents that increase local adenosine concentrations, such as dipyridamole, an agent that blocks the adenosine taken up by the cells, prevents bone loss following tenofovir treatment depending on intact adenosine A2A receptor signaling [23]. As Sema4D is a key modulator of bone turnover and plays an important role in HIV immunity, and knowing that tenofovir diminished BMD in HIV patients, we, hypothesize that Sema4D signaling might be activated under tenofovir treatment, and increasing extracellular adenosine concentration with dipyridamole may counteract this effect by the activation of adenosine A2A receptor
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