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

描述（由申请人提供）：过度的破骨细胞活性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，如双膦酸盐和denosumab（抗rankl抗体），主要集中在抑制破骨细胞功能。此外，越来越清楚的是，破骨细胞是整个骨重塑所必需的，治疗性消除可能弊大于利。因此，为了提高治疗效果，了解参与骨重塑过程的细胞信号网络对于确定更有效的治疗靶点至关重要。bmp，目前用于治疗促进骨愈合和再生，已经被我们和其他人证明与RANKL（负责激活破骨细胞的主要细胞因子）协同作用，以促进破骨细胞的发生。bmp可以通过非规范的MAPK信令和规范的Smad 1/5信令发出信号。我们实验室之前的数据表明，当单核前体融合成多核破骨细胞时，phospho-SMAD 1/5在破骨细胞中的表达增加。我使用Cathepsin-Cre小鼠生成了破骨细胞中Smad 1和5有条件缺失的小鼠，以检验Smad 1/5表达对于破骨细胞融合和活性是必要的这一假设。其次，我生成的初步数据表明，肌球蛋白X（一种负责调节破骨细胞密封区模式的非常规肌球蛋白）的表达随着破骨细胞BMP2的刺激而增加，并且是Smad 1/5的下游靶点。在完成我提出的实验后，我希望能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，从而发现可用于抑制破骨细胞功能的潜在新治疗靶点。

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.