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: 8849297
• 负责人: Amy Tasca
• 金额: $ 6.95万
• 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/8849297
• 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; targeted treatment; 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（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，如双磷酸盐和地诺塞麦（抗 RANKL 抗体），重点是抑制破骨细胞功能。此外，越来越清楚的是，破骨细胞是整体骨重塑所必需的，治疗性消除可能弊大于利。因此，为了改善治疗结果，了解骨重塑过程中涉及的细胞信号网络对于确定更有效的治疗靶点非常重要。我们和其他人已经证明，BMP 目前在治疗上用于促进骨愈合和再生，它与 RANKL（负责激活破骨细胞的主要细胞因子）具有协同作用，以增强破骨细胞生成。 BMP 可以通过非规范 MAPK 信号传导和规范 Smad 1/5 信号传导发出信号。我们实验室之前的数据表明，当单核前体细胞融合成多核破骨细胞时，破骨细胞中磷酸-SMAD 1/5 的表达增加。我使用组织蛋白酶-Cre 小鼠生成了破骨细胞中 Smad 1 和 5 有条件删除的小鼠，以测试 Smad 1/5 表达对于破骨细胞融合和活性是必需的这一假设。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 BMP2 对破骨细胞的刺激而增加，并且是 Smad 1/5 的下游靶标。在完成我提出的实验后，我希望更好地了解破骨细胞分化，特别是破骨细胞融合过程中的分化，从而发现可用于抑制破骨细胞功能的潜在新治疗靶点。