The role of MyosinX in BMPs promotion of SMAD 1/5 in osteoclast formation and fun

描述(申请人提供)：过度的破骨细胞活动可导致病理性骨吸收，这是许多临床疾病的严重后果，包括骨质疏松症、转移性骨病和牙周病。因此，目前的治疗方法如双磷酸盐和迪诺单抗(抗RANKL抗体)主要集中在抑制破骨细胞功能上。此外，越来越清楚的是，破骨细胞是整个骨重建所必需的，而治疗性消除可能弊大于利。因此，为了改善治疗结果，了解参与骨重建过程的细胞信号网络对于确定更有效的治疗靶点具有重要意义。BMPS目前被用于促进骨愈合和再生，我们和其他人已经证明，它与RANKL协同作用，促进破骨细胞的生成。RANKL是负责激活破骨细胞的主要细胞因子。BMP可以通过非规范的MAPK信号和规范的Smad1/5信号传递信号。我们实验室以前的数据显示，在单核前体细胞与多核破骨细胞融合时，磷酸化Smad1/5在破骨细胞中的表达增加。我用组织蛋白酶-Cre小鼠产生了破骨细胞中Smad1和Smad5的有条件缺失的小鼠，以测试Smad1/5表达对于破骨细胞融合和活动是必要的这一假设。其次，我已经生成了初步的数据，证明了肌球蛋白X的表达随着破骨细胞的BMP2刺激而增加，并且是Smad1/5的下游靶点。肌球蛋白X是一种负责调节破骨细胞封闭区图案的非传统肌球蛋白。在我拟议的实验完成后，我希望更好地了解破骨细胞的分化，特别是在破骨细胞融合过程中，从而发现可以用于抑制破骨细胞功能的潜在的新的治疗靶点。

DESCRIPTION (provided by applicant): Excessive osteoclast activity can lead to pathological bone resorption, which is a serious consequence of many clinical diseases including, osteoporosis, metastastic bone disease and periodontal disease. Therefore, current therapies such as bisphosphonates and denosumab (anti-RANKL antibody) have focused on inhibiting osteoclast function. Furthermore, it is becoming clear that osteoclasts are required for overall bone remodeling, and therapeutic elimination may cause more harm than good. Therefore, to improve treatment outcomes, understanding the cellular signaling networks involved in bone remodeling process is important to identifying more effective therapeutic targets. BMPs, which are currently used therapeutically to promote bone healing and regeneration, have been shown by us and others to act synergistically with RANKL, the main cytokine responsible in activating osteoclasts, to enhance osteoclastogenesis. BMPs can signal through both noncanonical MAPK signaling and canonical Smad 1/5 signaling. Previous data from our lab has shown that phospho-SMAD 1/5 expression increases in osteoclasts at the time of fusion of mononuclear precursors into multinucleated osteoclasts. I have generated mice that are conditionally deleted for Smad 1 and 5 in osteoclasts using the Cathepsin-Cre mice to test the hypothesis that Smad 1/5 expression is necessary for osteoclast fusion and activity. Secondly, I have generated preliminary data demonstrating that the expression of myosin X, an unconventional myosin responsible for regulating the sealing zone patterning in osteoclasts, increases with BMP2 stimulation of osteoclasts and is a downstream target of Smad 1/5. At the completion of my proposed experiments I expect to better understand osteoclast differentiation, particularly during osteoclast fusion and thereby uncover potential novel therapeutic targets that can be used to inhibit osteoclast function.