The goal of these studies is to understand the effects that the systemic regulatory factor, parathyroid hormone (PTH), has on the migration and homing to bone of circulating osteoclast precursor cells. Rationale: Osteoclasts are unique cells that resorb bone and are coregulators (with osteoblasts) of bone turnover, bone mass and bone quality. However, we have only limited knowledge of what steps are involved in their maturation. Specifically, this application will focus on the question of what path osteoclast precursors take to migrate to bone. Currently, it is unknown whether osteoclast precursor cells, which originate in bone marrow, 1) migrate directly from bone marrow to adjacent bone, where they mature and function as resorbing cells or if they 2) first migrate from the bone marrow to the circulation, undergo a maturation step extramedullary and then return to bone to become resorbing cells. It is also unclear whether systemic regulators of bone homeostasis like PTH alter the bone marrow microenvironment and increase the circulation and homing of osteoclast precursors to bone. It is also possible that both pathways are important and that endosteal and trabecular bone remodeling at sites adjacent to bone marrow are regulated by the pathway 1, while periosteal resorption and osteoclast formation at sites not adjacent to bone marrow are dependent on pathway 2. By studying the lineage progression, migration patterns and factors that regulate the homing of osteoclast precursor cells to bone in normal and pathologic conditions, we hope to better understand the role that circulating cells, which retain the capacity to develop into osteoclasts, have in bone physiology. It is anticipated that this knowledge will identify new targets for interventions, which can be used to create therapies to reverse bone loss, improve bone quality and prevent the morbidities that are associated with the development of osteoporosis and other metabolic bone diseases.
Specific Aim 1 : Define the population of osteoclast precursor cells in the bone marrow and periphery (blood and spleen) and determine if parathyroid hormone (PTH) treatment in vivo alters their relative proportions or absolute number in mice.
Specific Aim 2 : Determine if osteoclast precursor cells migrate extramedullarily and then home to bone in the basal state or after treatment of mice with parathyroid hormone.

Public Health Relevance

These studies will examine the relevance of extramedullary circulation in the maturation of osteoclasts, which are the only cells capable of efficiently resorbing bone. By studying the lineage progression, migration patterns and factors that regulate the homing of osteoclast precursor cells to bone in normal and pathologic conditions, we hope to better understand the role that circulating cells, which retain the capacity to develop into osteoclasts, have in bone physiology. It is anticipated that this knowledge will identify new targets for interventions, which can be used to create therapies to reverse bone loss, improve bone quality and prevent the morbidities that are associated with the development of osteoporosis and other metabolic bone diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048714-06
Application #
7597015
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Sharrock, William J
Project Start
2002-08-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
6
Fiscal Year
2009
Total Cost
$325,600
Indirect Cost
Name
University of Connecticut
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
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Jacome-Galarza, Christian E; Lee, Sun-Kyeong; Lorenzo, Joseph A et al. (2013) Identification, characterization, and isolation of a common progenitor for osteoclasts, macrophages, and dendritic cells from murine bone marrow and periphery. J Bone Miner Res 28:1203-13
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Jacome-Galarza, Christian E; Lee, Sun-Kyeong; Lorenzo, Joseph A et al. (2011) Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow. J Bone Miner Res 26:1207-16
Horowitz, Mark C; Fretz, Jackie A; Lorenzo, Joseph A (2010) How B cells influence bone biology in health and disease. Bone 47:472-9
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Horowitz, Mark C; Lorenzo, Joseph A (2007) Immunologic regulation of bone development. Adv Exp Med Biol 602:47-56
Lorenzo, Joseph (2007) Osteoclast precursor cells. Adv Exp Med Biol 602:77-82

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