Runx2 and Axin2 Interactions During Bone Formation

描述（由申请人提供）：该项目探讨了骨修复/再生和最佳骨量积累和维持的两个关键调节因子之间的分子和生理相互作用：Runx 2和Axin 2。Runx 2（Cbfa 1）是成骨细胞生成和软骨细胞肥大所需的转录因子。Runx 2缺陷是出生后致死的，而Runx 2单倍不足导致锁骨颅骨发育不良（CCD）和骨质减少。至少部分挽救Runx 2小鼠中表型的唯一已知生物学手段是通过抑制Gsk 3 - 2。Axin 2是一种浓度限制性支架蛋白，其将Gsk 3 -2，2-连环蛋白和其他组分组装成2-连环蛋白破坏复合物。Axin 2是经典Wnt信号传导的负反馈调节剂，并减缓成骨细胞增殖。有趣的是，Axin 2敲除小鼠具有高的骨小梁质量。因此，Axin 2缺陷和Runx 2单倍不足导致相反的骨小梁表型。我们表明，Axin 2水平在Runx 2缺陷细胞中增加。该项目的中心假设是Runx 2通过积极抑制Axin 2和增强骨细胞中的Wnt/2-catenin信号传导来促进骨量和强度。本提案的目的是定量评估“双突变”Runx 2：Axin 2-/-小鼠相对于“单突变”Runx 2或Axin 2-/-小鼠的表型，并确定Runx 2和Axin 2之间的相互作用是否调节骨细胞分化。 公共卫生相关性：该项目探讨了骨修复/再生和最佳骨量积累和维持的两个关键调节因子之间的分子相互作用：Runx 2和Axin 2。该项目具有重要意义，因为Runx 2是成骨细胞生成所必需的，而Axin 2是Wnt-2-catenin信号通路的关键负调节因子，Wnt-2-catenin信号通路是新合成代谢药物的靶点。因为Axin 2是2-连环蛋白和Lrp 5信号传导的细胞内抑制剂，所以其活性理论上可以降低中和细胞外Wnt/Lrp 5/6抑制剂的新兴合成代谢疗法的效率（例如，抗硬化蛋白或抗Dkk 1抗体）。对Runx 2和Axin 2之间相互作用的更多理解将产生集体影响，因为Runx 2和Axin 2也有助于软骨细胞成熟，并且是肿瘤抑制因子。

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.