The role of efferocytic macrophages in bone formation
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ABSTRACT Skeletal disorders such as osteoporosis and fractures are extremely widespread and result in debilitation, high morbidity, and compromise in quality of life. Remodeling of the skeleton is a continuous process dependent on osteoblasts to form new mineralized matrix. Mesenchymal stem and progenitor cells (MSPC) and osteoblasts lining the endosteal surface undergo cell death by apoptosis, yet the consequences of osteoblast-lineage apoptotic bodies in the bone microenvironment are unknown. The endosteum abuts bone marrow, which is rich in cells of the myeloid lineage including osteal macrophages that play essential roles in bone development, tissue homeostasis, and wound healing and repair. A vital function of macrophages is their specialized phagocytosis of apoptotic cells (termed efferocytosis). In response to efferocytosis macrophages activate a transcriptional profile, which results in the production of specific cytokines/growth factors unique to the efferocytosed cell type. Macrophages adapt to environmental changes in correlation with specialized alterations in their transcriptional profile. The project hypothesis is that bone marrow macrophage efferocytosis of apoptotic osteoblast-lineage cells induces an inflammation-resolving response including the attraction of MSPCs to the endosteal surface and new bone formation. Three specific aims will dissect these mechanisms using novel animal models. Aim one will identify the role of bone marrow macrophages in recruiting MSPCs to the bone-forming surface. The second aim will elucidate the osteoblastic differentiation stage dependence for macrophage driven efferocytosis and bone formation using a novel apoptosis induction mouse model that will target osteoblast cell death in progenitors, differentiated osteoblasts, and mature osteoblast/osteocytes. The third aim will determine the impact of facilitating macrophage efferocytosis and resolution of inflammation on bone formation using a specialized pro-resolving mediator lipoxinA4 (LXA4). The impact of LXA4 in the clearance of apoptotic osteoblast-lineage cells and its ability to modulate inflammation and recruit MSPCs during osseous healing will be determined. Detailed analyses of bone marrow macrophage function as well as skeletal phenotyping will provide deeper mechanistic insights as well as translational potential. New cellular and molecular information will be garnered from this project as well as strategic discernment of bone remodeling and regeneration to inform therapeutic approaches for metabolic bone disease and local osseous wound healing.
