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Abstract Number: 1990

Tenofovir Modulates Semaphorin 4D Signaling and Regulates Bone Homeostasis, Which Can Be Counteracted by Dipyridamole and Adenosine A2A Receptor

Aranzazu Mediero1, Patricia Llamas-Granda 2, Bruce Cronstein 3, Raquel Largo 4 and Gabriel Herrero-Beaumont 4, 1IIS-FUNDACION JIMENEZ DIAZ, Madrid, Spain, 2IIS-FUNDACION JIMENEX DIAZ, Madrid, Spain, 3Department of Medicine, Division of Rheumatology NYUSoM, NYC, 4IIS-Fundación Jiménez Díaz, Madrid, Madrid, Spain

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: adenosine receptors and Sema4D, bone remodeling, Cell Signaling, Osteoblasts

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Session Information

Date: Tuesday, November 12, 2019

Session Title: Osteoarthritis & Joint Biology – Basic Science Poster

Session Type: Poster Session (Tuesday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Semaphorins (Sema) are a family of proteins associated with neuronal development and guidance. Sema4D/CD100 was first identified as a regulator of immune response in resting T cells and NK cells. It has been recently found that loss of CD100 expression plays an important role in dysfunctional immunity in HIV infection. Osteopenia has been associated with HIV infection. Tenofovir, one of the most commonly used antivirals in HIV, increases in bone catabolism markers and decreased bone mineral density (BMD). Sema4D is secreted by osteoclasts (OC) in the presence of RANKL and binds to its receptor PlexinB1 on osteoblasts (OB) to inhibit their differentiation and function by activating RhoA/ROCK. Adenosine A2AR activation inhibits Sema4D-mediated OC activation and diminishes inflammatory osteolysis. We have recently described that treatment with agents that increase local adenosine concentrations, like dipyridamole, prevent bone loss following tenofovir treatment in vivo and in vitro. We hypothesized that Sema4D signaling might be regulated by tenofovir to alter bone turnover, and dipyridamole may counteract this effect.

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 OC and stimulated OB were challenge with Tenofovir 1mM alone or with dipyridamole 1mM, and expression of Sema4D/PlexinB1, RhoA/ROCK and b-catenin were study by Western Blot and inmmunostaining (n=3-4). OB differentiation was studied by alizarin red staining.

Results: Mice treated with tenofovir showed an increased expression of Sema4D and its receptor PlexinB1 when comprare to control mice, and treatment with dipyridamole reverted the expression of these molecules. In vitro, tenofovir inhibits OB differentiation and treatment with dipyridamole reversed this effect. In OC, tenofovir increases Sema4D expression (1191±32% increase vs basal, p< 0.05) and secretion (51±20% increase vs basal, p< 0.05) 24 hours after stimulation, and pretreatment with dipyridamole reverted this effect. No changes in PlexinB1 expression were observed in OB. Both total b-catenin and de-phospho b-catenin (active) were increased in the cytoplasmic fraction and decreased in the nuclear fraction in OB 15 minutes after treatment with tenofovir and this was reverted in the presence of dipyridamole. Phosphorilation of RhoA was increased in OB by tenofovir 10 minutes after treatment (32±11% increase vs. basal, p< 0.05) and reverted by dipyridamole, and ROCK1 was increased by tenofovir 15 minutes after treatment (83±35% increase vs. basal, p< 0.05), and dipyridamole decreases the expression as well.

Conclusion: These results suggest that tenofovir increases bone loss by activation Sema4D/PlexinB1 signaling that inhibis OB differentiation. Treatment with agents that increase local adenosine concentrations, like dipyridamole, might prevent this bone loss following inhibition of the pathway and increase of OB differentiation.


Disclosure: A. Mediero, None; P. Llamas-Granda, None; B. Cronstein, Abbott, 4, Amgen, AstraZeneca, 5, Baxter, 4, Bristol-Myers Squibb, 4, CanFite Biopharma, 4, Eli Lilly & Co, 5, Gilead, 4, Horizon Pharmaceuticals, 5, NIH, Arthritis Foundation, Kairos, 2, Novartis, 4, Patent Pending for the use of adenosine receptor agonists for the treatment of OA, Patents pending for use of adenosine receptor agonist and antagonist for treatment of bone, liver diseases and wound healing, Regenosine, 4, Regenosine, Inc, 4, 6; R. Largo, None; G. Herrero-Beaumont, None.

To cite this abstract in AMA style:

Mediero A, Llamas-Granda P, Cronstein B, Largo R, Herrero-Beaumont G. Tenofovir Modulates Semaphorin 4D Signaling and Regulates Bone Homeostasis, Which Can Be Counteracted by Dipyridamole and Adenosine A2A Receptor [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/tenofovir-modulates-semaphorin-4d-signaling-and-regulates-bone-homeostasis-which-can-be-counteracted-by-dipyridamole-and-adenosine-a2a-receptor/. Accessed April 13, 2021.
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