Sclerostin Mutant with Selective Binding to LRP4 Activates Wnt Pathway and Promotes Bone Anabolic Functions

Svetlana Katchkovsky, Niv Papo, Noam Levaot

Research output: Contribution to journalMeeting Abstract

1 Scopus citations

Abstract

The Wnt signaling pathway plays an essential role in bone homeostasis and is finely tuned by a complex interplay between Wnt ligands, receptors, activators and inhibitors. Wnt induction of bone formation is inhibited upon binding of sclerostin, a glycoprotein produced by osteocytes, to the Wnt receptors LRP5/6. Binding of sclerostin to additional receptor LRP4 is required to facilitate optimal inhibition. Herein, we show that a sclerostin mutant (sclerostinN93A) with high binding affinity to LRP4 but not LRP5/6 antagonizes wild-type sclerostin (sclerostinWT) inhibition of Wnt signaling pathway in vitro in osteoblast cultures.
In order to increase retention of sclerostinN93A we fused the Fc domain of immunoglobulin G to the C-terminal of sclerostinN93A (sclerostinN93AFc). We show that this modification does not interfere with its ability to antagonize sclerostinWT. Finally, we show that bi-weekly subcutaneous injections of sclerostinN93AFc for two weeks significantly increase trabecular volumetric bone fraction and bone length in developing mice. Our data suggest that compounds that target sclerostin LRP4 binding interface could serve as a potential strategy to promote bone anabolic functions.
Original languageEnglish GB
Pages (from-to)258-258
JournalJournal of Bone and Mineral Research
Volume35
Issue numberS1
DOIs
StatePublished - Nov 2020

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