Mechanism of a mimetic peptide CK2.3 on bone formation

描述(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膦酸盐。新的治疗方法，如甲状旁腺素，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会导致破骨细胞活性的增加，从而增加骨转换。在临床上，除了甲状旁腺素外，还可以通过使用双膦酸类药物来避免这种情况。目前尚无增强成骨、减少破骨细胞生成和/或破骨细胞活性的单一疗法，但迫切需要。我们建议确定一种新的多肽CK2.3在体外和体内促进成骨、降低破骨细胞生成和破骨细胞活性的机制。细胞中加入CK2.3可激活BMP2信号通路，促进细胞矿化。在小鼠的头盖骨和尾部注射CK2.3可增加骨密度(BMD)。与BMP2形成鲜明对比的是，小鼠尾部注射CK2.3或CK2.3刺激细胞，在体内和体外都抑制了破骨细胞的活性。治疗性的CK2.3刺激一种强大的生长因子BMP2的不同途径。CK2.3被设计用来阻断BMP Ia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，必须探索该肽的确切机制。使用BMPs治疗骨质疏松症的一个主要缺点是长期影响，导致骨转换增加。此外，众所周知，BMP2可以刺激破骨细胞的生成。患者对BMP2的反应显示出几种副作用，BMP2作为一种治疗方法并不是很有效。根据我们已发表的初步数据，CK2.3可能是一种可用于治疗骨质疏松症的独特疗法。这项提案的目标是确定CK2.3的机制。即使CK2.3可能不适合作为治疗骨质疏松症的药物，它也为破译治疗骨质疏松症的新途径和靶点开辟了新的途径。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.