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.