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: 8906474
• 负责人: ANJA G NOHE
• 金额: $ 33.15万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8906474
• 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）：骨质疏松症的常用治疗方法包括抑制破骨细胞活性的双磷酸盐。较新的治疗方法，如甲状旁腺激素，侧重于增强成骨细胞的活性。然而，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导致破骨细胞活性的增加，从而增加骨更新。在临床上，除了甲状旁腺激素外，还可以通过使用双膦酸盐来避免这种情况。一种促进成骨和降低破骨细胞生成和/或破骨细胞活性的单一治疗方法目前尚不可用，但迫切需要。我们建议在体外和体内确定一种新的肽CK2.3促进成骨和降低破骨细胞生成和破骨细胞活性的机制。在细胞中添加CK2.3可激活BMP2信号通路和矿化。将CK2.3注射到小鼠颅骨和尾部，可增加骨密度（BMD）。与BMP2形成鲜明对比的是，小鼠尾静脉注射CK2.3或CK2.3刺激细胞可抑制体内和体外破骨细胞活性。治疗性CK2.3刺激强大的生长因子BMP2的不同途径。CK2.3旨在阻断BMP Ia型受体（BMPRIA）和酪蛋白激酶2 （CK2）之间的相互作用，从而激活特定的BMP2信号通路。然而，这种肽的确切机制还有待探索。使用bmp作为骨质疏松症治疗的一个主要缺点是长期影响导致骨更新增加。此外，已知BMP2可刺激破骨细胞生成。患者对BMP2的反应显示出一些副作用，BMP2作为一种治疗方法不是很有效。根据我们发表的和初步的数据，CK2.3可能是一种独特的治疗骨质疏松症的药物。本提案的目标是确定CK2.3的机制。即使CK2.3可能不适合作为骨质疏松症的治疗方法，它也为骨质疏松症的治疗开辟了新的途径和靶点。迫切需要新的治疗方法。