The maintenance of healthy bones in adults requires coordinated bone turnover where bone formation is closely coupled to bone resorption, allowing bone renewal with the maintenance of bone mass. Uncoupling of bone formation and bone resorption underlies the loss of bone mass seen in a variety of conditions including aging, the menopause, and various inflammatory disorders such as rheumatoid arthritis (RA). These disorders are generally associated with enhanced bone resorption accompanied by rates of bone formation that are inadequate for the level of resorption. Anti-resorptive therapies have been the traditional approach for treating patients with low bone mass in these conditions, but it is increasingly recognized that anabolic therapies that enhance bone formation constitute an important alternative strategy. Previous studies have identified that inhibitory G protein (Gi) signaling in osteoblast lineage cells suppresses bone formation and is an important driver of age-related bone loss in females, but the factors that are upstream of this signaling pathway are unknown. Suppression of canonical Wnt signaling in osteoblast lineage cells is also linked to reduced bone formation. The present study will use a variety of mouse models to test the hypothesis that progranulin (PGRN), an inflammation-associated factor produced by macrophages and implicated in age-related bone loss, is a critical upstream regulator of inflammatory cytokine production and that PGRN-mediated cytokine production promotes bone loss through activation of Gi signaling and suppression of canonical Wnt signaling in osteoblast lineage cells. This hypothesis will be tested in three specific aims. In Specific Aim 1, the role of PGRN in bone marrow macrophage (BMM)-regulated bone formation will be explored. To accomplish this, we will determine whether alternations in the population of BMMs accounts for promotion of bone resorption by PGRN; whether expression of PGRN reduces the pro- osteogenic activity of BMMs; and whether transplantation of BMMs from PGRN-deficient mice can protect or reverse bone loss in adult female mice. Specific Aim 2 will address the role of suppression of anabolic signaling pathways in the negative effects of PGRN on bone formation. The role of the canonical Wnt pathway will be investigated in vivo in mice with targeted deletion of Ctnnb1, the gene encoding b-catenin, and will be investigated in vitro in osteoblast lineage cells lacking expression of PGRN. The ability of PGRN to inhibit Gs/cyclic AMP signaling will be assessed in vitro in cultured osteocytes and in vivo in its ability to limit the anabolic response to intermittent PTH administration. Specific Aim 3 is a translational aim in which we will explore the role of PGRN in mediating bone loss in two disorders associated with inflammation- rheumatoid arthritis (RA) and estrogen deficiency-induced osteoporosis. We will determine whether PGRN deficient mice are protected from bone loss after ovariectom...