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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Autores principales:	Patricia Llamas-Granda, Laura Martin-Rodríguez, Raquel Largo, Gabriel Herrero-Beaumont, Aránzazu Mediero
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Sema4D tenofovir bone turnover HIV adenosine A2A receptor osteoblast Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/73f8e5acad59435e9fc5b741753ed5da
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spelling	oai:doaj.org-article:73f8e5acad59435e9fc5b741753ed5da2021-11-11T16:57:13ZTenofovir Modulates Semaphorin 4D Signaling and Regulates Bone Homeostasis, Which Can Be Counteracted by Dipyridamole and Adenosine A2A Receptor10.3390/ijms2221114901422-00671661-6596https://doaj.org/article/73f8e5acad59435e9fc5b741753ed5da2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11490https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Semaphorin 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.Patricia Llamas-GrandaLaura Martin-RodríguezRaquel LargoGabriel Herrero-BeaumontAránzazu MedieroMDPI AGarticleSema4Dtenofovirbone turnoverHIVadenosine A2A receptorosteoblastBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11490, p 11490 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Sema4D tenofovir bone turnover HIV adenosine A2A receptor osteoblast Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	Sema4D tenofovir bone turnover HIV adenosine A2A receptor osteoblast Biology (General) QH301-705.5 Chemistry QD1-999 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
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.
format	article
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
title	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_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_sort	tenofovir modulates semaphorin 4d signaling and regulates bone homeostasis, which can be counteracted by dipyridamole and adenosine a2a receptor
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/73f8e5acad59435e9fc5b741753ed5da
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Tenofovir Modulates Semaphorin 4D Signaling and Regulates Bone Homeostasis, Which Can Be Counteracted by Dipyridamole and Adenosine A2A Receptor

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