Bone anabolic effects of osteoclast-produced phospho-Wnt5a

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Project Summary There is still a need to identify new efficacious and cost effective anabolic bone drugs to treat osteopenic conditions, bone fragility and repair. The goal of this application is to establish a phosphorylated form of Wnt5a produced by osteoclasts as a clastokine, capable of enhancing bone formation in vivo. This comes with the translational promise to deliver phosphomimetic Wnt5a peptide as an anabolic drug to promote osteogenesis in the future. The proposed work is premised on our compelling preliminary evidence that conditional deletion of Wnt5a from osteoclasts (OCLs) resulted in decreased bone mass, which was concomitant with decreased bone formation rate in vivo. We further discovered a specific Ser phosphorylation of Wnt5a in osteoclastic cells. This phospho-Wnt5a or its mimetic mutant proteins promoted osteogenesis. We therefore hypothesize that a phosphorylated form of Wnt5a, produced by OCL but not OBs, serve as a clastokine to promote anabolic bone formation. To verify this hypothesis, we will: first establish the in vivo control of OB function by OCL- produced Wnt5a and determine the skeletal consequences of Wnt5a over-expression in OCL-precursors (First Aim). We will then reveal the cellular and molecular mechanisms via which a post-translationally modified form of Wnt5a produced by OCL control OB function in vitro and in vivo. Finally, we will generate induced pluripotent stem cells expressing phospho-defective and -mimetic Wnt5a mutants via genome editing to promote bone formation in a murine critical sized calvarial defect (Second Aim).