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.

描述（由申请人提供）：该项目探讨了骨修复/再生的两个关键调节因子与最佳骨质量应计和维护之间的分子和生理相互作用：Runx2和Axin2。 Runx2（CBFA1）是骨基细胞生成和软骨细胞肥大所需的转录因子。 Runx2缺乏性是在产后致命的，而Runx2-Haploinsunsusicy会导致Cleidockanial发育不良（CCD）和骨质骨减少症。至少部分部分挽救Runx2小鼠表型的唯一已知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，将GSK3-2，2-catenin和其他成分组装成2-catenin销毁的蛋白质。 Axin2是典型Wnt信号传导的负反馈调节器，并减慢成骨细胞增殖。有趣的是，AXIN2敲除小鼠的小梁骨量很高。因此，AXIN2缺乏和Runx2-链纤维不足会导致对立的小梁骨表型。我们表明，RUNX2缺陷型细胞中AXIN2水平增加。该项目的中心假设是Runx2通过主动抑制AXIN2并增强骨细胞中的Wnt/2-catenin信号来促进骨骼和强度。该建议的目的是定量评估“双突变体” Runx2：axin2 - / - 小鼠相对于“单个突变体” 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的相互作用。 公共卫生相关性：该项目探讨了两个关键的骨修复/再生调节剂与最佳骨质量应计和维护之间的分子相互作用：Runx2和Axin2。该提出的项目很重要，因为runx2是成骨细胞生成所必需的，而Axin2是Wnt-2-catenin信号通路的关键负调节剂，这是新代谢剂的靶标。由于AXIN2是2-catenin和LRP5信号传导的细胞内抑制剂，因此从理论上讲，其活性可以降低中和细胞外Wnt/LRP5/6抑制剂的新代谢疗法的效率（例如，抗固定蛋白或抗固醇或抗DKK1抗体）。人们对Runx2和Axin2之间的相互作用的了解将产生集体影响，因为RUNX2和AXIN2也有助于软骨细胞的成熟，并且是肿瘤抑制剂。