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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).

项目摘要仍然需要鉴定新的有效的和成本有效的合成代谢骨药物来治疗骨质疏松症。条件，骨脆弱性和修复。本申请的目的是建立Wnt 5a的磷酸化形式由破骨细胞产生，作为一种断裂因子，能够增强体内骨形成。这是随附的翻译的承诺，提供磷酸模拟Wnt5a肽作为合成代谢药物，以促进骨生成，未来建议的工作是基于我们令人信服的初步证据，有条件删除来自破骨细胞（OCL）的Wnt 5a导致骨量减少，这伴随着骨减少。体内形成率。我们进一步发现破骨细胞中Wnt 5a的特异性Ser磷酸化。这磷酸化Wnt5a或其模拟突变体蛋白促进骨生成。因此，我们假设，由OCL而不是OB产生的磷酸化形式的Wnt5a作为断裂因子促进合成代谢骨形成为了验证这一假设，我们将：首先建立OCL对OB功能的体内控制，产生Wnt5a并确定Wnt5a在OCL前体中过表达的骨骼后果（第一次 Aim）。然后，我们将揭示细胞和分子机制，通过该机制， OCL产生的Wnt 5a在体外和体内控制OB功能。最后，我们将产生诱导多能通过基因组编辑表达磷酸缺陷和模拟Wnt5a突变体以促进骨形成的干细胞在鼠临界大小的颅骨缺损中形成（第二目标）。