Runx2 and Axin2 Interactions During Bone Formation

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。

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.