Proper bone maintenance and bone structure is crucial for women health. Osteoporosis and low bone mineral density have a tremendous negative impact on the physical, emotional, and mental wellbeing of postmenopausal women. One out of two women will be diagnosed with Osteoporosis in their lifetime. More women die from osteoporosis each year than die from breast cancer and ovarian cancer combined. Bone Morphogenetic Protein 2 (BMP2) is a growth factor that is essential for osteogenesis, increases osteoblast activity and enhances bone formation. BMP2 is explored as a treatment option for fracture healing and bone diseases. Although, BMP2 is effective in multiple animal models, it is less successful in the clinic. The response of patients to BMP2 shows several side effects and BMP2 is not very effective as a treatment. We recently identified the interaction of Casein Kinase II (CK2) with the BMP Receptor Type Ia (BMPRIa). We developed a peptide, namely CK2.3, that releases CK2 from the receptor and activates BMP2 signaling in the absence of BMP2. CK2.3 is more specific compared to BMP2 by activating only a subset of the BMP2 signaling pathways. Knockout of BMPRIa by CRISPR/CAS, demonstrates that CK2.3 signals through BMPRIa. CK2.3 specifically induces bone formation by driving osteogenesis and increasing osteoblast activity while decreasing osteoclastogenesis and osteoclast activity. BMP2 signaling is aberrant in osteoblasts from patients diagnosed with Osteoporosis (POP). Osteoblasts or explants isolated from femoral heads of POP do not respond to BMP2 by increasing markers for osteoblast activity and mineralization. However, CK2.3 treatment of osteoblasts from POP leads to an increase in mineralization. At the same time CK2.3 decreases osteoclastogenesis and osteoclast activity. The goal of this proposal is to determine the cause of the lack of responsiveness of osteoblasts to BMP2 while they still respond to CK2.3. Osteoblasts from POP overexpress BMPRIa, followed by downregulation after BMP2 stimulation. However, the BMP2 signaling pathway downstream of the receptor is not activated. These data suggest that the problem is localized to BMPRIa shuttling on the plasma membrane, degradation, or recycling. Since CK2.3 acts through BMPRIa and still activates the signaling pathway, we will define the role of CK2.3 in overcoming the lack in BMPRIa signaling. BMP2 is an essential growth factor in osteogenesis and bone formation. Understanding the pathways identified in this proposal is crucial to define new dogmas in bone biology and develop new successful treatments for bone diseases. Further, CK2.3 by itself may be a potential therapeutic.