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A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and α(v)β(3) integrin for osteoporosis therapy
There is currently a demand for new highly efficient and specific drugs to treat osteoporosis, a chronic bone disease affecting millions of people worldwide. We have developed a combinatorial strategy for engineering bispecific inhibitors that simultaneously target the unique combination of c-FMS an...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126843/ https://www.ncbi.nlm.nih.gov/pubmed/30142160 http://dx.doi.org/10.1371/journal.pbio.2002979 |
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author | Zur, Yuval Rosenfeld, Lior Keshelman, Chen Anna Dalal, Nofar Guterman-Ram, Gali Orenbuch, Ayelet Einav, Yulia Levaot, Noam Papo, Niv |
author_facet | Zur, Yuval Rosenfeld, Lior Keshelman, Chen Anna Dalal, Nofar Guterman-Ram, Gali Orenbuch, Ayelet Einav, Yulia Levaot, Noam Papo, Niv |
author_sort | Zur, Yuval |
collection | PubMed |
description | There is currently a demand for new highly efficient and specific drugs to treat osteoporosis, a chronic bone disease affecting millions of people worldwide. We have developed a combinatorial strategy for engineering bispecific inhibitors that simultaneously target the unique combination of c-FMS and α(v)β(3) integrin, which act in concert to facilitate bone resorption by osteoclasts. Using functional fluorescence-activated cell sorting (FACS)-based screening assays of random mutagenesis macrophage colony-stimulating factor (M-CSF) libraries against c-FMS and α(v)β(3) integrin, we engineered dual-specific M-CSF mutants with high affinity to both receptors. These bispecific mutants act as functional antagonists of c-FMS and α(v)β(3) integrin activation and hence of osteoclast differentiation in vitro and osteoclast activity in vivo. This study thus introduces a versatile platform for the creation of new-generation therapeutics with high efficacy and specificity for osteoporosis and other bone diseases. It also provides new tools for studying molecular mechanisms and the cell signaling pathways that mediate osteoclast differentiation and function. |
format | Online Article Text |
id | pubmed-6126843 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-61268432018-09-17 A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and α(v)β(3) integrin for osteoporosis therapy Zur, Yuval Rosenfeld, Lior Keshelman, Chen Anna Dalal, Nofar Guterman-Ram, Gali Orenbuch, Ayelet Einav, Yulia Levaot, Noam Papo, Niv PLoS Biol Research Article There is currently a demand for new highly efficient and specific drugs to treat osteoporosis, a chronic bone disease affecting millions of people worldwide. We have developed a combinatorial strategy for engineering bispecific inhibitors that simultaneously target the unique combination of c-FMS and α(v)β(3) integrin, which act in concert to facilitate bone resorption by osteoclasts. Using functional fluorescence-activated cell sorting (FACS)-based screening assays of random mutagenesis macrophage colony-stimulating factor (M-CSF) libraries against c-FMS and α(v)β(3) integrin, we engineered dual-specific M-CSF mutants with high affinity to both receptors. These bispecific mutants act as functional antagonists of c-FMS and α(v)β(3) integrin activation and hence of osteoclast differentiation in vitro and osteoclast activity in vivo. This study thus introduces a versatile platform for the creation of new-generation therapeutics with high efficacy and specificity for osteoporosis and other bone diseases. It also provides new tools for studying molecular mechanisms and the cell signaling pathways that mediate osteoclast differentiation and function. Public Library of Science 2018-08-24 /pmc/articles/PMC6126843/ /pubmed/30142160 http://dx.doi.org/10.1371/journal.pbio.2002979 Text en © 2018 Zur et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Zur, Yuval Rosenfeld, Lior Keshelman, Chen Anna Dalal, Nofar Guterman-Ram, Gali Orenbuch, Ayelet Einav, Yulia Levaot, Noam Papo, Niv A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and α(v)β(3) integrin for osteoporosis therapy |
title | A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and α(v)β(3) integrin for osteoporosis therapy |
title_full | A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and α(v)β(3) integrin for osteoporosis therapy |
title_fullStr | A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and α(v)β(3) integrin for osteoporosis therapy |
title_full_unstemmed | A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and α(v)β(3) integrin for osteoporosis therapy |
title_short | A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and α(v)β(3) integrin for osteoporosis therapy |
title_sort | dual-specific macrophage colony-stimulating factor antagonist of c-fms and α(v)β(3) integrin for osteoporosis therapy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126843/ https://www.ncbi.nlm.nih.gov/pubmed/30142160 http://dx.doi.org/10.1371/journal.pbio.2002979 |
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