Functional variants of RUNX2 related to bone density

骨密度和骨质疏松症有遗传因素。确定与骨密度有关的基因可能有助于控制骨质疏松症。我们已经在一种叫做RUNX2的基因中发现了一种变体，它与骨密度有关，这种骨密度足以保护个体四倍免受科勒骨折的伤害，科勒骨折是女性常见的手腕骨折。该变异与RUNX2的第二个启动子的变化高度相关，因此高骨密度形式似乎是该基因的祖先形式。我们现在需要知道这个启动子的变化是如何改变骨密度的，我们正在跟踪观察其他重要的转录因子与启动子中的可变位点结合。此外，我们收集了大量骨密度和关节炎患者的样本，以便准确测量该基因对骨密度、骨关节炎和骨折的影响。此外，一些髋部骨折或骨密度低的人也有这种基因的突变。这种被称为Q-repeat区域的突变相当普遍，1-200人是携带者。我们的数据表明，这些突变蛋白在调节其他基因的任务中效率不高。我们现在想知道这是如何在分子意义上发生的，因为我们知道Runx2蛋白位于细胞核中，并与许多其他调节因子相互作用。该项目的这一部分是由一位研究骨细胞基因调控的世界专家完成的。由于RUNX2是制造骨骼的细胞的主要调节因子，这就给了通过这种主要调节因子来改变骨骼形成的希望。

Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone density may permit advances in controlling osteoporosis. We have identified a variant in a gene called RUNX2 that is related to bone density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in women. This variant is highly correlated with changes in the second promoter of RUNX2, such that the high bone density form appears to be the ancestral form of this gene. We now need to know how this change in this promoter alters bone density and we are following up on observations that other important transcription factors bind to the variable site in the promoter. Furthermore, we have assembled a large collection of samples from people who have had extensive measures of bone density and arthritis in order to accurately measure the impact of this gene on bone density, osteoarthritis and bone fracture. In addition, some people with bone fracture at the hip, or low bone density, have mutations in this gene. Such mutations in a region called the Q-repeat are rather common, 1-200 people are carriers. Our data show that these mutant proteins are not as efficient at their task of regulating other genes. We now want to know how this occurs in a molecular sense, since it is known that the Runx2 protein resides in the nucleus of the cell and interacts with many other regulators. This part of the project is being done with one of the world experts on gene regulation in bone cells. Since RUNX2 is a master regulator of the cells that make bone, this gives hope that it may be possible to alter bone formation through this master regulator.