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Bone anabolic effects of osteoclast-produced phospho-Wnt5a

破骨细胞产生的磷酸化 Wnt5a 的骨合成代谢作用

基本信息

批准号：
10929243
负责人：
HICHAM M DRISSI
金额：
$ 31.3万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-18 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10929243
关键词：
Biological Biological Assay Bone Marrow Bone Resorption Bone remodeling CRISPR/Cas technology Calvaria Cells Clinical Coculture Techniques Data Data Set Defect Encapsulated Evaluation Female Fracture Future Genes Genotype Goals Harvest Histologic Homeostasis Hydrogels Image In Vitro LoxP-flanked allele Macrophage Mediating Modeling Molecular Molecular Analysis Mus Myeloid Cells Osteoblasts Osteoclasts Osteogenesis Osteoporotic Outcome Measure Ovariectomy Paracrine Communication Peptides Pharmaceutical Preparations Phenocopy Phenotype Phosphorylation Post-Translational Protein Processing Production Proteins Role Signal Pathway Site-Directed Mutagenesis Skeletal Development Surface System TNFSF11 gene Tamoxifen Transgenic Mice Visualization Work Zebrafish bone bone fragility bone loss bone mass bone repair cost effective experimental study fracture risk gain of function genome editing in vivo induced pluripotent stem cell laser capture microdissection loss of function male microCT mimetics mutant novel therapeutic intervention osteoclastogenesis osteogenic overexpression paracrine phenotypic biomarker prevent response skeletal substantia spongiosa trafficking transcriptome sequencing

项目摘要

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).

项目总结