Saturday, November 23, 2024
11/23/2024
PROJECT SUMMARY Leptin, originally identified as a regulator of energy metabolism, is required for normal bone growth and turnover, making the adipokine an attractive candidate for coupling optimal bone accrual and turnover balance to energy availability. However, not all skeletal actions of leptin are beneficial; there is compelling evidence that leptin contributes to aging-related skeletal pathologies by promoting a proinflammatory cascade mediating inflammation-driven bone loss. The molecular mechanisms mediating the skeletal actions are poorly defined. We have strong preliminary data indicating that leptin influences bone metabolism, both beneficially and detrimentally, by activating leptin receptor (OB-R) on cells (predominately immune cells) derived from hematopoietic stem cells (HSCs). Based on this, we hypothesize that: (1) leptin signaling by immune cells is necessary for normal bone growth, maturation and turnover, but (2) in the presence of chronic inflammation, leptin signaling by immune cells promotes net bone loss. The proposed research will test these hypotheses in male and female mice by accomplishing two Specific Aims. Specific Aim 1: Determine the contribution of leptin signaling by immune cells to bone accrual and turnover balance. We will reconstitute the immune system of growing and adult male and female mice with HSCs from OB-R+ wild type (WT) or OB-R- db/db mice using adoptive transfer to establish the overall contribution of OB-R on immune cells to leptin regulation of bone accrual in growing mice and turnover balance in adult mice, respectively. We will then determine if the skeletal actions of leptin are primarily mediated via OB-R on cells in the osteoclast lineage by adoptively transferring OB-R+ and OB-R- monocytes into mice with reduced ability to form osteoclasts (Ccr2- mice). Specific Aim 2: Determine the contribution of leptin signaling by immune cells to inflammation-driven bone loss. We will reconstitute the immune system of growing and adult male and female mice with HSCs from OB-R+ or OB-R- mice as in Specific Aim 1 and induce local inflammation by placing polyethylene particles over calvaria to model aseptic periprosthetic bone loss. These studies will establish the overall contribution of OB-R on immune cells to inflammation-driven bone loss. The contribution of OB-R on immune cell subsets to normal bone turnover balance and particle-induced osteolysis in adult mice will then be evaluated following engraftment of subsets of OB-R+ and OB-R- immune cells into mice unable to generate/recruit monocytes (Ccr2-), T-cells (Tcra KO), B-cells (muMT-), or mast cells (KitW-sh). Successful completion of this research will have a major impact on the field by expanding existing concepts regarding the role of leptin in skeletal health and disease. Our approach will provide a powerful tool for unraveling mechanisms mediating the complex actions of leptin on the skeleton and immune systems. The proposed research has the potential to provide new insights for the development of interventions to interrupt leptin-mediated inflammatory cascades without compromising the beneficial skeletal actions of the adipokine.
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