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An antagonistic monoclonal anti–Plexin-B1 antibody exerts therapeutic effects in mouse models of postmenopausal osteoporosis and multiple sclerosis

Osteoporosis and multiple sclerosis are highly prevalent diseases with limited treatment options. In light of these unmet medical needs, novel therapeutic approaches are urgently sought. Previously, the activation of the transmembrane receptor Plexin-B1 by its ligand semaphorin 4D (Sema4D) has been...

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Autores principales: Vogler, Melanie, Oleksy, Arkadiusz, Schulze, Sabrina, Fedorova, Marina, Kojonazarov, Baktybek, Nijjar, Sharandip, Patel, Seema, Jossi, Sian, Sawmynaden, Kovilen, Henry, Maud, Brown, Richard, Matthews, David, Offermanns, Stefan, Worzfeld, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9396414/
https://www.ncbi.nlm.nih.gov/pubmed/35850304
http://dx.doi.org/10.1016/j.jbc.2022.102265
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author Vogler, Melanie
Oleksy, Arkadiusz
Schulze, Sabrina
Fedorova, Marina
Kojonazarov, Baktybek
Nijjar, Sharandip
Patel, Seema
Jossi, Sian
Sawmynaden, Kovilen
Henry, Maud
Brown, Richard
Matthews, David
Offermanns, Stefan
Worzfeld, Thomas
author_facet Vogler, Melanie
Oleksy, Arkadiusz
Schulze, Sabrina
Fedorova, Marina
Kojonazarov, Baktybek
Nijjar, Sharandip
Patel, Seema
Jossi, Sian
Sawmynaden, Kovilen
Henry, Maud
Brown, Richard
Matthews, David
Offermanns, Stefan
Worzfeld, Thomas
author_sort Vogler, Melanie
collection PubMed
description Osteoporosis and multiple sclerosis are highly prevalent diseases with limited treatment options. In light of these unmet medical needs, novel therapeutic approaches are urgently sought. Previously, the activation of the transmembrane receptor Plexin-B1 by its ligand semaphorin 4D (Sema4D) has been shown to suppress bone formation and promote neuroinflammation in mice. However, it is unclear whether inhibition of this receptor–ligand interaction by an anti–Plexin-B1 antibody could represent a viable strategy against diseases related to these processes. Here, we raised and systematically characterized a monoclonal antibody directed against the extracellular domain of human Plexin-B1, which specifically blocks the binding of Sema4D to Plexin-B1. In vitro, we show that this antibody inhibits the suppressive effects of Sema4D on human osteoblast differentiation and mineralization. To test the therapeutic potential of the antibody in vivo, we generated a humanized mouse line, which expresses transgenic human Plexin-B1 instead of endogenous murine Plexin-B1. Employing these mice, we demonstrate that the anti–Plexin-B1 antibody exhibits beneficial effects in mouse models of postmenopausal osteoporosis and multiple sclerosis in vivo. In summary, our data identify an anti–Plexin-B1 antibody as a potential therapeutic agent for the treatment of osteoporosis and multiple sclerosis.
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spelling pubmed-93964142022-08-25 An antagonistic monoclonal anti–Plexin-B1 antibody exerts therapeutic effects in mouse models of postmenopausal osteoporosis and multiple sclerosis Vogler, Melanie Oleksy, Arkadiusz Schulze, Sabrina Fedorova, Marina Kojonazarov, Baktybek Nijjar, Sharandip Patel, Seema Jossi, Sian Sawmynaden, Kovilen Henry, Maud Brown, Richard Matthews, David Offermanns, Stefan Worzfeld, Thomas J Biol Chem Research Article Osteoporosis and multiple sclerosis are highly prevalent diseases with limited treatment options. In light of these unmet medical needs, novel therapeutic approaches are urgently sought. Previously, the activation of the transmembrane receptor Plexin-B1 by its ligand semaphorin 4D (Sema4D) has been shown to suppress bone formation and promote neuroinflammation in mice. However, it is unclear whether inhibition of this receptor–ligand interaction by an anti–Plexin-B1 antibody could represent a viable strategy against diseases related to these processes. Here, we raised and systematically characterized a monoclonal antibody directed against the extracellular domain of human Plexin-B1, which specifically blocks the binding of Sema4D to Plexin-B1. In vitro, we show that this antibody inhibits the suppressive effects of Sema4D on human osteoblast differentiation and mineralization. To test the therapeutic potential of the antibody in vivo, we generated a humanized mouse line, which expresses transgenic human Plexin-B1 instead of endogenous murine Plexin-B1. Employing these mice, we demonstrate that the anti–Plexin-B1 antibody exhibits beneficial effects in mouse models of postmenopausal osteoporosis and multiple sclerosis in vivo. In summary, our data identify an anti–Plexin-B1 antibody as a potential therapeutic agent for the treatment of osteoporosis and multiple sclerosis. American Society for Biochemistry and Molecular Biology 2022-07-15 /pmc/articles/PMC9396414/ /pubmed/35850304 http://dx.doi.org/10.1016/j.jbc.2022.102265 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Vogler, Melanie
Oleksy, Arkadiusz
Schulze, Sabrina
Fedorova, Marina
Kojonazarov, Baktybek
Nijjar, Sharandip
Patel, Seema
Jossi, Sian
Sawmynaden, Kovilen
Henry, Maud
Brown, Richard
Matthews, David
Offermanns, Stefan
Worzfeld, Thomas
An antagonistic monoclonal anti–Plexin-B1 antibody exerts therapeutic effects in mouse models of postmenopausal osteoporosis and multiple sclerosis
title An antagonistic monoclonal anti–Plexin-B1 antibody exerts therapeutic effects in mouse models of postmenopausal osteoporosis and multiple sclerosis
title_full An antagonistic monoclonal anti–Plexin-B1 antibody exerts therapeutic effects in mouse models of postmenopausal osteoporosis and multiple sclerosis
title_fullStr An antagonistic monoclonal anti–Plexin-B1 antibody exerts therapeutic effects in mouse models of postmenopausal osteoporosis and multiple sclerosis
title_full_unstemmed An antagonistic monoclonal anti–Plexin-B1 antibody exerts therapeutic effects in mouse models of postmenopausal osteoporosis and multiple sclerosis
title_short An antagonistic monoclonal anti–Plexin-B1 antibody exerts therapeutic effects in mouse models of postmenopausal osteoporosis and multiple sclerosis
title_sort antagonistic monoclonal anti–plexin-b1 antibody exerts therapeutic effects in mouse models of postmenopausal osteoporosis and multiple sclerosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9396414/
https://www.ncbi.nlm.nih.gov/pubmed/35850304
http://dx.doi.org/10.1016/j.jbc.2022.102265
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