Mechanism of a mimetic peptide CK2.3 on bone formation

模拟肽CK2.3对骨形成的机制

• 批准号: 8630192
• 负责人: ANJA G NOHE
• 金额: $ 32.98万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630192
• 关键词: Adverse effects; Affect; American; Bone Density; Bone Resorption; Calvaria; Cells; Clinic; Data; Development; Event; Exhibits; Fracture; Genes; Goals; Growth Factor; In Vitro; Injection of therapeutic agent; Lead; Mediating; Medical; Minerals; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Pathway interactions; Patients; Peptides; Population; Publishing; Quality of life; Signal Pathway; Signal Transduction; Tail; Testing; Therapeutic; Therapeutic Agents; Woman; analog; base; bisphosphonate; bone; bone cell; bone loss; bone mass; bone morphogenetic protein 2; bone morphogenetic protein receptor type I; bone morphogenetic protein receptor type II; bone turnover; casein kinase II; common treatment; cost; density; design; in vitro activity; in vivo; men; mimetics; mineralization; novel; novel therapeutics; osteoclastogenesis; prevent; protein protein interaction; public health relevance; receptor; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Common treatments for osteoporosis include bisphosphonates, which inhibit osteoclast activity. Newer treatments such as PTH focus on enhancing osteoblast activity. However, due to the crosstalk between osteoblasts and osteoclasts an increase of osteoblast activity may lead to increased osteoclast activity and therefore increased bone turnover. In the clinic this is circumvented by administering bisphosphonates in addition to PTH. A single therapeutic that enhances osteogenesis and decreases osteoclastogenesis and/or osteoclast activity is currently unavailable, but is desperately needed. We propose to determine the mechanism of a new peptide CK2.3 that enhances osteogenesis and decreases osteoclastogenesis and osteoclast activity in vitro and in vivo. Addition of CK2.3 to cells leads to the activation of BMP2 signaling pathways and mineralization. Injection of CK2.3 into calvaria, as well as in the tail vain of mice, increases boe mineral density (BMD). In sharp contrast to BMP2, stimulation of cells with CK2.3 or CK2.3 injection into the tail vain of mice inhibits osteoclast activity in vivo and in vitro. The therapetic CK2.3 stimulates distinct pathways of a powerful growth factor BMP2. CK2.3 is designed to block the interaction between the BMP type Ia receptor (BMPRIA) and Casein Kinase 2 (CK2) leading to activation of specific BMP2 signaling pathways. However, the exact mechanism of the peptide must be explored. A major drawback of the use of BMPs as osteoporosis treatment is the long term affect that causes increased bone turnover. Additionally, BMP2 is known to stimulate osteoclastogenesis. The response of patients to BMP2 shows several side effects and BMP2 is not very effective as a treatment. Based on our published and preliminary data CK2.3 maybe a unique therapeutic that can be used for the treatment of osteoporosis. The goal of this proposal is to determine the mechanism of CK2.3. Even if CK2.3 may not be suitable as a therapeutic for osteoporosis it opens new ways to decipher new pathways and targets for osteoporosis treatment. New therapeutics are desperately needed.

描述（由申请人提供）：骨质疏松症的常见治疗方法包括抑制骨细胞活性的双膦酸盐。诸如PTH之类的新疗法专注于增强成骨细胞活性。但是，由于成骨细胞和破骨细胞之间的串扰，成骨细胞活性的增加可能会导致破骨细胞活性增加，因此增加了骨转换。在诊所中，除PTH外，还可以通过给予双膦酸盐来规避这一点。目前不可用，可增强成骨并降低破骨细胞生成和/或破骨细胞活性的单一治疗性，但迫切需要。我们建议确定一种新肽CK2.3的机制，从而增强骨生成并降低体外和体内破骨细胞生成和破骨细胞活性。在细胞中添加CK2.3导致BMP2信号通路和矿化的激活。将CK2.3注入瓦尔瓦里亚以及小鼠的尾巴中，增加了BOE矿物质密度（BMD）。与BMP2形成鲜明对比的是，用CK2.3或CK2.3注入小鼠尾部的细胞刺激细胞抑制了体内和体外的破骨细胞活性。治疗CK2.3刺激了强大生长因子BMP2的不同途径。 CK2.3旨在阻止BMP IA受体（BMPRIA）和酪蛋白激酶2（CK2）之间的相互作用，从而导致特定BMP2信号通路的激活。但是，必须探索肽的确切机制。使用BMP作为骨质疏松症治疗的主要缺点是导致骨转换增加的长期影响。另外，已知BMP2刺激破骨细胞生成。患者对BMP2的反应显示出几种副作用，而BMP2作为治疗效果不太有效。基于我们发表的初步数据CK2.3，也许是一种独特的治疗性，可用于治疗骨质疏松症。该提案的目的是确定CK2.3的机制。即使CK2.3可能不适合作为骨质疏松症的治疗性，它也为破译新途径和骨质疏松治疗的靶标开了新的方法。迫切需要新的治疗剂。