Runx2 and Axin2 Interactions During Bone Formation

描述(由申请人提供)：这个项目探索了两个关键的骨修复/再生调节因子和最佳骨量增加和维持之间的分子和生理相互作用：Runx2和Axin2。Runx2(Cbfa1)是成骨细胞形成和软骨细胞肥大所必需的转录因子。Runx2缺乏症是出生后致命的，而Runx2单倍体缺乏症会导致锁骨颅骨发育不良和骨量减少。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是一种浓度限制的支架蛋白，它将GSK3-2，2-catenin和其他成分组装成2-catenin破坏复合体。Axin2是典型的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，Axin2基因敲除小鼠的骨小梁质量很高。因此，Axin2缺乏和Runx2单倍体缺乏导致相反的骨小梁表型。我们发现，在Runx2缺陷的细胞中，Axin2水平增加。该项目的中心假设是，Runx2通过主动抑制Axin2和增强骨细胞中的Wnt/2-catenin信号来促进骨量和强度。这项建议的目的是定量评估“双突变”Runx2：Axin2-/-小鼠相对于“单一突变”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。 与公共健康相关：这个项目探索了两个关键的骨修复/再生调节因子和最佳骨量积累和维持之间的分子相互作用：Runx2和Axin2。这项拟议的项目意义重大，因为Runx2是成骨细胞形成所必需的，而Axin2是Wnt-2-catenin信号通路的关键负调控因子，而Wnt-2-catenin信号通路是新的合成代谢药物的靶标。由于Axin2是2-连环素和LRP5信号的细胞内抑制物，理论上它的活性可能会降低新出现的中和细胞外Wnt/LRP5/6抑制物(如抗硬化素或抗Dkk1抗体)的合成代谢疗法的效率。进一步了解Runx2和Axin2之间的相互作用将产生集体影响，因为Runx2和Axin2也有助于软骨细胞成熟，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.