Parathyroid hormone (PTH) is well known for its anabolic actions in bone and is an effective therapeutic agent for the treatment of osteoporosis and localized osseous defects. Despite its clinical efficacy, its mechanisms of action are complex and elusive in particular in regard to its potential for regenerative approaches and wound healing. A key aspect of the complexity is that PTH anabolic actions are not the simple activation of osteoblasts, but require accessory cells in an intricate temporal and spatial organization. Data from the previous project award strongly support the ability of PTH to act on bone in an indirect manner through myeloid cells in the bone marrow microenvironment. The overall hypothesis of this project is that PTH acts via macrophage engulfment of apoptotic osteoblasts to produce coupling factors that recruit mesenchymal stem cells to form new bone. The specific phagocytosis of apoptotic cells is termed efferocytosis and is emerging as an integral process in tissue homeostasis, inflammation, autoimmunity and cancer, yet virtually nothing has been investigated regarding its role in the bone microenvironment. On a daily basis there are billions of cells undergoing apoptosis in the human body. Exposure of adjacent cells to the contents of dead and dying cells results in harmful inflammatory responses, yet when macrophages engulf apoptotic cells they release anti-inflammatory factors such as TGF? that are instrumental in recruiting mesenchymal stem cells. Macrophages utilize distinct receptor signaling pathways to identify apoptotic cells for efferocytosis. Such identification and signaling events represent intriguing and focused new pharmacologic targets to benefit bone regenerative strategies.
Three specific aims will dissect the ability of apoptotic osteoblasts to recruit phagocytic myeloid cells, the dependence of PTH anabolic actions on macrophage phagocytosis, the specific mediators on apoptotic and myeloid cells that facilitate efferocytosis and how these link to anabolic actions of PTH in bone. This proposal will delineate these pathways relative to osteoblast apoptosis and the support of new bone formation. This is a novel new coupling paradigm in bone - macrophages - efferyocytosing apoptotic osteoblasts - producing mesenchymal stem cell recruitment factors. Such a paradigm demonstrates a significant new step in the cell biologic processes in bone as well as robust potential for new avenues of therapeutic advantage for metabolic and inflammatory-mediated bone disease.

Public Health Relevance

Parathyroid hormone (PTH) is currently used in humans to stimulate bone growth in patients with osteoporosis and shows potential for situations where wound healing in bone is needed;however, the mechanisms of how it works to build and facilitate healing in bone are not clear. PTH also stimulates cells in the bone marrow (i.e. specia types of blood cells) and the relationship between these cells and bone cells is unknown. This project will investigate the mechanisms of action of PTH relative to its ability to stimulate bone cell renewal through a cycle whereby dying cells provide signals to specialized blood cells which trigger them to recruit new bone forming cells. This information and innovation is critical in orde to elucidate the clinical potential of therapies to assist in bone healing.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK053904-14A1
Application #
8577232
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
Project Start
1998-08-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
14
Fiscal Year
2013
Total Cost
$326,550
Indirect Cost
$116,550
Name
University of Michigan Ann Arbor
Department
Dentistry
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Cho, Sun Wook; Soki, Fabiana N; Koh, Amy J et al. (2014) Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone. Proc Natl Acad Sci U S A 111:1545-50
McCauley, Laurie K; Dalli, Jesmond; Koh, Amy J et al. (2014) Cutting edge: Parathyroid hormone facilitates macrophage efferocytosis in bone marrow via proresolving mediators resolvin D1 and resolvin D2. J Immunol 193:26-9
Novince, Chad M; Entezami, Payam; Wilson, Christopher G et al. (2013) Impact of proteoglycan-4 and parathyroid hormone on articular cartilage. J Orthop Res 31:183-90
Cho, Sun Wook; Pirih, Flavia Q; Koh, Amy J et al. (2013) The soluble interleukin-6 receptor is a mediator of hematopoietic and skeletal actions of parathyroid hormone. J Biol Chem 288:6814-25
Soki, Fabiana N; Li, Xin; Berry, Janice et al. (2013) The effects of zoledronic acid in the bone and vasculature support of hematopoietic stem cell niches. J Cell Biochem 114:67-78
Chan, H L; McCauley, L K (2013) Parathyroid hormone applications in the craniofacial skeleton. J Dent Res 92:18-25
Danciu, Theodora E; Li, Yan; Koh, Amy et al. (2012) The basic helix loop helix transcription factor Twist1 is a novel regulator of ATF4 in osteoblasts. J Cell Biochem 113:70-9
Motyl, Katherine J; McCauley, Laurie K; McCabe, Laura R (2012) Amelioration of type I diabetes-induced osteoporosis by parathyroid hormone is associated with improved osteoblast survival. J Cell Physiol 227:1326-34
McCauley, Laurie K; Martin, T John (2012) Twenty-five years of PTHrP progress: from cancer hormone to multifunctional cytokine. J Bone Miner Res 27:1231-9
Novince, Chad M; Koh, Amy J; Michalski, Megan N et al. (2011) Proteoglycan 4, a novel immunomodulatory factor, regulates parathyroid hormone actions on hematopoietic cells. Am J Pathol 179:2431-42

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