A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 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 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.

journal_name

PLoS Biol

journal_title

PLoS biology

authors

Zur Y,Rosenfeld L,Keshelman CA,Dalal N,Guterman-Ram G,Orenbuch A,Einav Y,Levaot N,Papo N

doi

10.1371/journal.pbio.2002979

subject

Has Abstract

pub_date

2018-08-24 00:00:00

pages

e2002979

issue

8

eissn

1544-9173

issn

1545-7885

pii

pbio.2002979

journal_volume

16

pub_type

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