Osteoporosis (porous bone disease) is a disease of the skeleton that can have debilitating effects on many US veterans. An estimated 44 million Americans, or 55 percent of the people 50 years of age and older, are currently at risk for osteoporotic fracture. Improved treatment options for the disease require a greater understanding of the cellular events and signaling pathways that control bone metabolism. The proposed research capitalizes on a recently identified secreted inhibitor of Wnt glycoproteins. The long-term goal of the proposed project is to investigate whether targeting a new, secreted inhibitor of Wnt signaling—Notum--can improve bone properties and reduce fracture susceptibility. In the first aim we propose to determine the cell type in which Notum inhibition exerts its effects on bone homeostasis, by crossing conditional Notum mutant mice to different Cre drivers that are active during different stages of the mesenchymal cell lineage. We will also look the gene expression changes induced by Notum inhibition to see if the canonical Wnt pathway, the noncanonical Wnt pathway, the Hedgehog pathway, or some other pathway, is primarily affected. We will also identify downstream nodes in the pathways altered by Notum inhibition, to see if there are more readily targetable effectors of the HBM phenotype induced by Notum inhibition. I the second aim, we will conduct functional studies targeting Notum, which has direct applicability to future therapeutic approaches in patients. Glucocorticoids are widely used among the veteran population for numerous conditions, including organ transplant, rheumatoid arthritis, inflammatory bowel disease, and others, but side effects are not trivial, and bone wasting is a major concern among glucocorticoid-treated patients. Likewise, mechanical disuse is a major problem among veterans, which results from long term bedrest, paralysis, and other complications. We will inhibit Notum in these preclinical models to determine whether Notum inhibition represents a viable strategy for preserving bone mass and function during two relevant bone wasting conditions. In this renewal Merit application, we address these questions in order to identify new ways to improve bone health among the veteran population, and among the public in general.