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

MyosinX在BMPs促进SMAD 1/5破骨细胞形成和乐趣中的作用

• 批准号: 8782667
• 负责人: Amy Tasca
• 金额: $ 6.84万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-27 至 2016-05-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8782667
• 关键词: Antibodies; BMP2 gene; Bone Diseases; Bone Marrow; Bone Matrix; Bone Morphogenetic Proteins; Bone Regeneration; Bone Resorption; Bone Transplantation; Bone remodeling; Cathepsins; Cell surface; Cells; Clinical; Data; Development; Disease; Endothelial Cells; Excision; Fracture; Gene Expression; Generations; Healed; In Vitro; Knock-out; Lead; Lentivirus Vector; MAP Kinase Gene; Malignant Neoplasms; Mediating; Molecular; Mononuclear; Mus; Myosin ATPase; Open Fractures; Orthopedics; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Pathogenesis; Pathway interactions; Pattern; Periodontal Diseases; Phenotype; Prevention; Procedures; Process; Publishing; Research; Reverse Transcriptase Polymerase Chain Reaction; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Staging; TRANCE protein; Testing; Therapeutic; Time; Trauma; Treatment outcome; Western Blotting; Work; bisphosphonate; bone; bone healing; bone loss; bone morphogenetic protein 9; bone morphogenetic protein receptors; cathepsin K; craniofacial; cytokine; gastrulation; healing; improved; in vivo; innovation; insight; knock-down; mouse model; new therapeutic target; novel; novel therapeutics; osteoclastogenesis; overexpression; protein expression; public health relevance; research study; seal; therapeutic target

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.

描述（由申请人提供）：破骨细胞活性过度可导致病理性骨吸收，这是许多临床疾病（包括骨质疏松症、骨质疏松性骨病和牙周病）的严重后果。因此，目前的治疗，如双膦酸盐和狄诺塞单抗（抗RANKL抗体），重点是抑制破骨细胞功能。此外，越来越清楚的是，破骨细胞是整个骨重建所必需的，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非常重要。BMP目前在治疗上用于促进骨愈合和再生，我们和其他人已经证明与RANKL（负责激活破骨细胞的主要细胞因子）协同作用，以增强破骨细胞生成。BMP可以通过非经典MAPK信号和经典Smad 1/5信号来进行信号传导。来自我们实验室的先前数据表明，在单核前体融合成多核破骨细胞时，破骨细胞中磷酸化SMAD 1/5表达增加。我用组织蛋白酶-Cre小鼠产生了破骨细胞中Smad 1和5有条件缺失的小鼠，以检验Smad 1/5表达对破骨细胞融合和活性是必要的这一假设。其次，我已经产生的初步数据表明，肌球蛋白X，一种非常规的肌球蛋白，负责调节破骨细胞的密封区图案的表达，增加与破骨细胞的BMP 2刺激，是Smad 1/5的下游目标。在完成我提出的实验，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，从而发现潜在的新的治疗目标，可用于抑制破骨细胞的功能。