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 collection of missense mutations in 2-propeller 1 of the LDL-receptor-related protein 5 (LRP5), recently identified in several human families, that have a major impact on bone mass regulation. The long term goal of the proposed project is to identify new molecular targets, yielded from novel mouse models engineered with those mutations, for pharmacologic intervention aimed at improving bone mass and reducing fracture susceptibility. LRP5 has been postulated to participate in the canonical WNT signaling cascade (e.g., GSK32-mediated modulation of 2- catenin activity) in vitro, but our recent data indicates that alterations in canonical WNT signaling might not account for the anabolic effects of the HBM mutations. Discovery of the mechanism by which Lrp5 controls bone formation would lead to new approaches for improving bone mass. In this application, we propose to determine whether 2-catenin is required for the bone formation effects of Lrp5. We will use two novel knock-in mouse models of HBM disease. These mice, which are modeled after two of the LRP5 HBM human families, have either the G171V or the A214V amino acid substitutions knocked in to Lrp5. The mutations result in very high bone mass, driven completely by increased bone formation, with no change in bone resorption. We will test whether these two mutations are associated with increased bone formation when 2- catenin is deleted. Further, we will determine whether the bone formation phenotype of Lrp5 knockout mice can be rescued by constitutive activation of 2-catenin. Subsequently, we will determine the mechanism of action for the G171V and A214V mutations, which appear to have fundamentally different effects at the cellular and tissue levels. In this Merit application, we address these questions in order to identify new Lrp5-associated anabolic targets for improving bone health.