Anabolic Mechanisms of PTH Action in Bone

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

ABSTRACT Parathyroid hormone (PTH) has been in clinical use as a therapeutic for more than ten years. Recently the FDA approved the second anabolic agent for the treatment of osteoporosis. Abaloparatide (a PTH-related protein/PTHrP analog) utilizes the same receptor as PTH with similar actions that stem from numerous and diverse activities in the bone microenvironment. PTH and PTHrP have shown anabolic potential in the treatment of localized osseous defects, but their application has been limited due to lack of understanding the totality of their actions. PTH stimulates cells of the myeloid lineage, a subset of which become osteal macrophages. Osteal macrophages stimulate bone formation via unknown mechanisms. The project hypothesis is that osteal macrophages engulf apoptotic osteoblastic cells and produce factors which recruit mesenchymal stem and progenitor cells (MSPCs) to the endosteal surface to initiate bone formation. Three specific aims will dissect the mechanisms using novel animal models and a translational approach that will provide a path toward new therapeutic strategies. Aim one will identify the role of the osteal macrophage in recruiting MSPCs to the bone forming surface. The second aim will elucidate the stage dependence of osteoblasts for macrophage driven efferocytosis and bone formation using a novel apoptosis induction 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 on bone formation and anabolic actions of PTH. A pro-resolving mediator that facilitates macrophage polarization and efferocytosis will be used to treat mice with an osteoporotic phenotype. Detailed analyses of osteal macrophage function as well as skeletal phenotyping will provide deeper mechanistic insight 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.