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 Bioljournal_title
PLoS biologyauthors
Zur Y,Rosenfeld L,Keshelman CA,Dalal N,Guterman-Ram G,Orenbuch A,Einav Y,Levaot N,Papo Ndoi
10.1371/journal.pbio.2002979subject
Has Abstractpub_date
2018-08-24 00:00:00pages
e2002979issue
8eissn
1544-9173issn
1545-7885pii
pbio.2002979journal_volume
16pub_type
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