Tenofovir Modulates Semaphorin 4D Signaling and Regulates Bone Homeostasis, Which Can Be Counteracted by Dipyridamole and Adenosine A2A Receptor
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...
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MDPI AG
2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/21/11490 |
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| author | Patricia Llamas-Granda Laura Martin-Rodríguez Raquel Largo Gabriel Herrero-Beaumont Aránzazu Mediero |
| author_facet | Patricia Llamas-Granda Laura Martin-Rodríguez Raquel Largo Gabriel Herrero-Beaumont Aránzazu Mediero |
| author_sort | Patricia Llamas-Granda |
| collection | DOAJ |
| description | 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. |
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| language | English |
| last_indexed | 2024-03-10T06:01:43Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-73f8e5acad59435e9fc5b741753ed5da2023-11-22T20:53:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122211149010.3390/ijms222111490Tenofovir Modulates Semaphorin 4D Signaling and Regulates Bone Homeostasis, Which Can Be Counteracted by Dipyridamole and Adenosine A2A ReceptorPatricia Llamas-Granda0Laura Martin-Rodríguez1Raquel Largo2Gabriel Herrero-Beaumont3Aránzazu Mediero4Bone and Joint Research Unit, IIS-Fundación Jiménez Díaz UAM, 28040 Madrid, SpainBone and Joint Research Unit, IIS-Fundación Jiménez Díaz UAM, 28040 Madrid, SpainBone and Joint Research Unit, IIS-Fundación Jiménez Díaz UAM, 28040 Madrid, SpainBone and Joint Research Unit, IIS-Fundación Jiménez Díaz UAM, 28040 Madrid, SpainBone and Joint Research Unit, IIS-Fundación Jiménez Díaz UAM, 28040 Madrid, SpainSemaphorin 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.https://www.mdpi.com/1422-0067/22/21/11490Sema4Dtenofovirbone turnoverHIVadenosine A2A receptorosteoblast |
| spellingShingle | Patricia Llamas-Granda Laura Martin-Rodríguez Raquel Largo Gabriel Herrero-Beaumont Aránzazu Mediero Tenofovir Modulates Semaphorin 4D Signaling and Regulates Bone Homeostasis, Which Can Be Counteracted by Dipyridamole and Adenosine A2A Receptor International Journal of Molecular Sciences Sema4D tenofovir bone turnover HIV adenosine A2A receptor osteoblast |
| title | Tenofovir Modulates Semaphorin 4D Signaling and Regulates Bone Homeostasis, Which Can Be Counteracted by Dipyridamole and Adenosine A2A Receptor |
| title_full | Tenofovir Modulates Semaphorin 4D Signaling and Regulates Bone Homeostasis, Which Can Be Counteracted by Dipyridamole and Adenosine A2A Receptor |
| title_fullStr | Tenofovir Modulates Semaphorin 4D Signaling and Regulates Bone Homeostasis, Which Can Be Counteracted by Dipyridamole and Adenosine A2A Receptor |
| title_full_unstemmed | Tenofovir Modulates Semaphorin 4D Signaling and Regulates Bone Homeostasis, Which Can Be Counteracted by Dipyridamole and Adenosine A2A Receptor |
| title_short | Tenofovir Modulates Semaphorin 4D Signaling and Regulates Bone Homeostasis, Which Can Be Counteracted by Dipyridamole and Adenosine A2A Receptor |
| title_sort | tenofovir modulates semaphorin 4d signaling and regulates bone homeostasis which can be counteracted by dipyridamole and adenosine a2a receptor |
| topic | Sema4D tenofovir bone turnover HIV adenosine A2A receptor osteoblast |
| url | https://www.mdpi.com/1422-0067/22/21/11490 |
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