? Project #2 We have recently shown that osteoblast-derived LCN2 suppresses appetite. At the same time, LCN2 is known as an acute phase response protein that following bacterial infections is highly increased in the serum. Since Lcn2 is primarily expressed by osteoblasts, we explored, whether osteoblast-derived LCN2 is an early sensor and regulator of inflammation. This response is of particular interest within the context of the aging population in which immune system responses are weakened and inflammation more common. Our preliminary data, using as a model of inflammatory response lipopolysaccharides (LPS) administration in mice, indicate that following an inflammatory stimulus, brain-derived signals rapidly stimulate osteoblasts to secrete LCN2 in the circulation. Release of LCN2 from osteoblasts is stimulated by glutamate and is regulated neuronally. This response is compromised with aging and may contribute to inflammation susceptibility with old age. Circulating LCN2 acts on key immune cells of the blood and other tissues and modulates their phenotype and subsequent function to contain endotoxemia, organ damage, and mortality. Based on these and other preliminary data, we hypothesize that bone is an acute inflammation-sensing organ that mounts lifesaving anti- inflammatory responses through LCN2 secretion by osteoblasts. To examine this hypothesis we will establish that osteoblast-derived LCN2 is required for mounting innate immune response using young and old adult mice with osteoblast-specific deletion of Lcn2 and models of LPS and bacterial infection and sepsis; inactivate the Grik5 receptor specifically in osteoblasts and examine whether it prevents LCN2 release in the serum after inflammation and exacerbates disease in young adult and in aging mice; establish the signaling pathway that originates in the brain and signals the release of LCN2 by osteoblasts in young adult and in aging mice. These studies will define a new function of bone as an acute inflammatory stressor and responder and delineate how the brain orchestrates a rapid response through bone and LCN2 to regulate systemic inflammation with aging.
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