Runx2 and Axin2 Interactions During Bone Formation

Runx2 和 Axin2 在骨形成过程中的相互作用

• 批准号: 8195738
• 负责人: Elizabeth W Bradley
• 金额: $ 5.3万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-04 至 2013-08-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195738
• 关键词: Adult; Affect; Anabolic Agents; Antibodies; Binding; Biology; Bone Marrow; Bone Regeneration; Bone Resorption; Calvaria; Cartilage; Cell Differentiation process; Cells; Chondrocytes; Cleidocranial Dysplasia; Coculture Techniques; Complex; Craniosynostosis; Defect; Development; Disease; Elements; Embryo; Embryonic Development; Exhibits; Feedback; Fellowship; Genetic Models; Genotype; Hypertrophy; In Vitro; Knock-out; Knockout Mice; Laboratories; Maintenance; Mediating; Mesenchymal Differentiation; Modeling; Molecular; Mus; Natural regeneration; Osteoblasts; Osteoclasts; Osteogenesis; Osteopenia; Phenotype; Physiological; Play; Postdoctoral Fellow; Process; Property; Relative (related person); Research; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Stromal Cells; Techniques; Testing; Tissues; Training; Tumor Suppressor Proteins; Work; X-Ray Computed Tomography; bone; bone cell; bone mass; bone strength; carcinogenesis; career; career development; density; extracellular; inhibitor/antagonist; intramembranous bone formation; long bone; macrophage; meetings; mouse development; mutant; osteoblast differentiation; postnatal; promoter; skeletal; skills; spine bone structure; substantia spongiosa; transcription factor

DESCRIPTION (provided by applicant): This project explores the molecular and physiological interactions between two crucial regulators of bone repair/regeneration and optimal bone mass accrual and maintenance: Runx2 and Axin2. Runx2 (Cbfa1) is a transcription factor required for osteoblastogenesis and chondrocyte hypertrophy. Runx2-deficiency is postnatally lethal, whereas Runx2-haploinsufficiency causes cleidocranial dysplasia (CCD) and osteopenia. The only known biologic means to at least partially rescue the phenotype in Runx2 mice is by inhibiting Gsk3- 2. Axin2 is a concentration-limiting scaffolding protein that assembles Gsk3-2, 2-catenin and other components into the 2-catenin destruction complex. Axin2 is a negative feedback regulator of canonical Wnt signaling and slows osteoblast proliferation. Interestingly, Axin2 knockout mice have high trabecular bone mass. Thus, Axin2-deficiency and Runx2-haploinsufficiency cause opposing trabecular bone phenotypes. We show that Axin2 levels are increased in Runx2-deficient cells. The central hypothesis of this project is that Runx2 promotes bone mass and strength by actively repressing Axin2 and enhancing Wnt/2-catenin signaling in bone cells. The objective of this proposal is to quantitatively assess the phenotypes of "double mutant" Runx2:Axin2-/- mice relative to "single mutant" Runx2 or Axin2-/- mice and to determine if the interaction between Runx2 and Axin2 regulates bone cell differentiation. PUBLIC HEALTH RELEVANCE: This project explores the molecular interactions between two crucial regulators of bone repair/regeneration and optimal bone mass accrual and maintenance: Runx2 and Axin2. The proposed project is significant because Runx2 is required for osteoblastogenesis and Axin2 is a crucial negative regulator of the Wnt-2-catenin signaling pathway, which is a target for new anabolic agents. Because Axin2 is an intracellular inhibitor of 2-catenin and Lrp5 signaling, its activity could theoretically decrease the efficiency of emerging anabolic therapies that neutralize extracellular Wnt/Lrp5/6 inhibitors (e.g., anti-Sclerostin or anti-Dkk1 antibodies). An increased understanding of the interactions between Runx2 and Axin2 will have a collective impact because Runx2 and Axin2 also contribute to chondrocyte maturation and are tumor suppressors.

项目描述（申请人提供）：本项目探讨骨修复/再生和最佳骨量积累和维持的两个关键调控因子Runx2和Axin2之间的分子和生理相互作用。Runx2 （Cbfa1）是成骨细胞发生和软骨细胞肥大所需的转录因子。runx2缺乏症在出生后是致命的，而runx2单倍体不足会导致锁骨颅发育不良（CCD）和骨质减少。唯一已知的至少部分挽救Runx2小鼠表型的生物学方法是抑制Gsk3- 2。Axin2是一种限制浓度的脚手架蛋白，它将Gsk3-2、2-catenin和其他组分组装成2-catenin破坏复合物。Axin2是典型Wnt信号的负反馈调节因子，可减缓成骨细胞的增殖。有趣的是，敲除Axin2的小鼠具有较高的骨小梁骨量。因此，axin2缺乏和runx2单倍不足导致相反的小梁骨表型。我们发现，在runx2缺陷细胞中，Axin2水平升高。该项目的中心假设是Runx2通过主动抑制Axin2和增强骨细胞中的Wnt/2-catenin信号传导来促进骨量和强度。本研究的目的是定量评估“双突变”Runx2:Axin2-/-小鼠相对于“单突变”Runx2或Axin2-/-小鼠的表型，并确定Runx2和Axin2之间的相互作用是否调节骨细胞分化。