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A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and ?v?3 integrin for osteoporosis therapy.


ABSTRACT: 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 ?v?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 ?v?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 ?v?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.

SUBMITTER: Zur Y 

PROVIDER: S-EPMC6126843 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 integrin for osteoporosis therapy.

Zur Yuval Y   Rosenfeld Lior L   Keshelman Chen Anna CA   Dalal Nofar N   Guterman-Ram Gali G   Orenbuch Ayelet A   Einav Yulia Y   Levaot Noam N   Papo Niv N  

PLoS biology 20180824 8


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  ...[more]

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