Bone Abstracts

The activation of Wnt signaling pathway is blocked by soluble proteins such as WIF-1, sFRP, Dkk1, and sclerostin, which work by sequestering the ligand (Wnt) or the co-receptor/receptor moiety. Recent advances in developing anti blocking agents such as monoclonal antibodies to the sclerostin and Dkk1 protein have generated significant interest as potentially useful approaches to treat patients that could utilize a rapid gain in bone mineral density in the context of osteoporosis. We have identified Wnt10b as a pertinent Wnt ligand in the context of bone which provides us with a very specific tool for studying the role of the Wnt pathway in regulating bone mass. More importantly, we have pursued the role of Wnt modulators, in regulating the cell fate of mesenchymal stem cells as they activate osteogenesis. These changes concomitantly result in decreased adipogenesis in the bone marrow microenvironment. Furthermore, while both PTH and Wnt signaling are effective in building a fracture callus by engaging in osteogenesis, they do so via distinct mechanisms that may partially overlap. Net bone gain can occur through modeling, or in imbalance in remodeling. The distinct mechanism of action of anti-sclerostin antibodies relies more on modeling versus an imbalance in remodeling, which is in contrast to PTH signaling. The consequence of this subtle difference may allow us to better identify patients who could benefit with either bone anabolic pathway.