Mechanism of a mimetic peptide CK2.3 on bone formation

描述（由申请人提供）：骨质疏松症的常见治疗包括双膦酸盐，其抑制破骨细胞活性。较新的治疗方法如PTH专注于增强成骨细胞活性。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，从而增加骨转换。在临床上，除了PTH之外，还可以通过给予双膦酸盐来避免这种情况。目前还没有一种能增强骨生成并降低破骨细胞生成和/或破骨细胞活性的单一治疗剂，但迫切需要这种治疗剂。我们建议确定一种新的肽CK2.3，增强成骨和减少破骨细胞生成和破骨细胞活性在体外和体内的机制。向细胞中添加CK2.3导致BMP 2信号通路的激活和矿化。将CK 2.3注射到小鼠的颅盖和尾静脉中，增加了骨密度（BMD）。与BMP 2形成鲜明对比的是，用CK2.3或CK2.3注射到小鼠尾静脉中刺激细胞在体内和体外抑制破骨细胞活性。治疗性CK2.3刺激强大的生长因子BMP 2的不同途径。CK2.3被设计为阻断BMP Ia型受体（BMPRIA）和酪蛋白激酶2（CK 2）之间的相互作用，导致特定BMP 2信号通路的激活。然而，必须探索肽的确切机制。使用BMP作为骨质疏松症治疗的一个主要缺点是长期影响，导致骨转换增加。此外，已知BMP 2刺激破骨细胞生成。患者对BMP 2的反应显示出一些副作用，并且BMP 2作为治疗不是非常有效。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方法，可用于治疗骨质疏松症。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药物，它也为解释骨质疏松症治疗的新途径和靶点开辟了新途径。迫切需要新的治疗方法。

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.