A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αv β3 integrin for osteoporosis therapy

Yuval Zur, Lior Rosenfeld, Chen Anna Keshelman, Nofar Dalal, Gali Guterman-Ram, Ayelet Orenbuch, Yulia Einav, Noam Levaot, Niv Papo

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 αv β3 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 αv β3 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 αv β3 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.

Original languageEnglish
Article numbere2002979
JournalPLoS Biology
Volume16
Issue number8
DOIs
StatePublished - 24 Aug 2018

ASJC Scopus subject areas

  • Neuroscience (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Immunology and Microbiology (all)
  • Agricultural and Biological Sciences (all)

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