A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 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...
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doaj-e4d2f8b01cd24d9797299590238fa6062021-07-02T03:58:51ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852018-08-01168e200297910.1371/journal.pbio.2002979A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 integrin for osteoporosis therapy.Yuval ZurLior RosenfeldChen Anna KeshelmanNofar DalalGali Guterman-RamAyelet OrenbuchYulia EinavNoam LevaotNiv PapoThere 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 αvβ3 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 αvβ3 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 αvβ3 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.http://europepmc.org/articles/PMC6126843?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yuval Zur Lior Rosenfeld Chen Anna Keshelman Nofar Dalal Gali Guterman-Ram Ayelet Orenbuch Yulia Einav Noam Levaot Niv Papo |
spellingShingle |
Yuval Zur Lior Rosenfeld Chen Anna Keshelman Nofar Dalal Gali Guterman-Ram Ayelet Orenbuch Yulia Einav Noam Levaot Niv Papo A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 integrin for osteoporosis therapy. PLoS Biology |
author_facet |
Yuval Zur Lior Rosenfeld Chen Anna Keshelman Nofar Dalal Gali Guterman-Ram Ayelet Orenbuch Yulia Einav Noam Levaot Niv Papo |
author_sort |
Yuval Zur |
title |
A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 integrin for osteoporosis therapy. |
title_short |
A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 integrin for osteoporosis therapy. |
title_full |
A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 integrin for osteoporosis therapy. |
title_fullStr |
A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 integrin for osteoporosis therapy. |
title_full_unstemmed |
A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 integrin for osteoporosis therapy. |
title_sort |
dual-specific macrophage colony-stimulating factor antagonist of c-fms and αvβ3 integrin for osteoporosis therapy. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Biology |
issn |
1544-9173 1545-7885 |
publishDate |
2018-08-01 |
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 αvβ3 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 αvβ3 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 αvβ3 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. |
url |
http://europepmc.org/articles/PMC6126843?pdf=render |
work_keys_str_mv |
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