Engineering Dual-Specific M-CSF Antagonists That Inhibit c-FMS And αvβ3 Integrin As Anti Resorptive Compounds

Yuval Zur, Lior Rosenfeld, Gali Guterman-Ram, Niv Papo, Noam Levaot

Research output: Contribution to journalMeeting Abstractpeer-review

1 Scopus citations

Abstract

Excessive and uncontrolled bone resorption by osteoclasts is a hallmark of many bone diseases, including osteoporosis. Therefore, controlled and specific inhibition of osteoclast activity is a desired outcome in treatments of bone diseases. Osteoclast differentiation and function are coordinated by cell surface receptors, including c-FMS and αvβ3 integrin, which cross talk with each other to drive signals that are essential for osteoclast functions. Using functional FACS-based screening assays of random mutagenesis M-CSF libraries against c-FMS and αvβ3 integrin, we engineered dual-specic M-CSF mutants with high anity to both receptors. We showed by SPR and cell surface binding assays that the engineered dual-specic M-CSF proteins can bind both αvβ3 integrin and c-FMS receptors, leading to antagonism of immediate signaling events (c-FMS and Akt phosphorylation) and down-stream biochemical events regulating osteoclast differentiation. Moreover, the dual-specific mutants had enhanced osteoclast inhibitory capabilities compared to inhibitors that target only one of the pathways, thereby highlighting the effects of the dual functionality that we engineered into these proteins. In the presence of the dual-specific inhibitors osteoclasts were unable to form a solid actin belt and were not able to differentiate properly in a dose dependent manner. Finally, we show that injection of the bispecific c-FMS and αvβ3 integrin proteins significantly inhibited bone resorption by osteoclasts in ovariectomized mice pro-viding proof of concept for their utilization as anti resorptive drugs.
Original languageEnglish GB
Pages (from-to)417-417
JournalJournal of Bone and Mineral Research
Volume33
Issue numberS1
DOIs
StatePublished - Nov 2018

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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