Runx2 and Axin2 Interactions During Bone Formation

描述（由申请人提供）：该项目探讨了颅面发育，骨修复/再生以及最佳骨量增加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。在Runx 2小鼠中至少部分挽救CCD表型的唯一已知生物学手段是通过抑制Gsk 32。Axin 2是将Gsk 32、2-连环蛋白和其它组分组装成2-连环蛋白破坏复合物的浓度限制性支架蛋白。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敲除小鼠具有颅缝早闭（CS）和高小梁骨质量密度。在人类中，AXIN 2突变与家族性牙齿发育不全有关。因此，Axin 2缺陷和Runx 2单倍不足导致相反的颅面和骨小梁表型。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主动抑制Axin 2以增强骨细胞中的Wnt/ 2-catenin信号传导。我们的目的是确定经典的Wnt信号是否在Runx 2-/-小鼠的成骨祖细胞中改变，定义Runx 2调节Axin 2转录的分子机制，并定量评估“双突变”Runx 2：Axin 2-/-小鼠相对于野生型、Runx 2和Axin 2-/-小鼠的骨骼表型。

DESCRIPTION (provided by applicant): This project explores the molecular and physiological interactions between two crucial regulators of craniofacial development, bone repair/regeneration, and optimal bone mass accrual and maintenance: Runx2 and Axin2. Runx2 (Cbfa1) is a transcription factor required for osteoblastogenesis and chondrocytes 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 CCD phenotype in Runx2 mice is by inhibiting Gsk32. Axin2 is the concentration- limiting scaffolding protein that assembles Gsk32, 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 craniosynostosis (CS) and high trabecular bone mass density. In humans, AXIN2 mutations are linked to familial tooth agenesis. Thus, Axin2-deficiency and Runx2- haploinsufficiency cause opposing craniofacial and trabecular bone phenotypes. We show that Axin2 levels are increased in Runx2-deficient cells. The central hypothesis of this project is that Runx2 actively represses Axin2 to enhance Wnt/ 2-catenin signaling in bone cells. We aim to determine if canonical Wnt signaling is altered in osteoblast progenitors from Runx2-/- mice, define the molecular mechanisms whereby Runx2 regulates Axin2 transcription, and to quantitatively assess the skeletal phenotypes of "double mutant" Runx2: Axin2-/- mice relative to wild type, Runx2 and Axin2-/- mice.