Bone is continuously remodeled throughout life, with complete skeletal turnover estimated to occur every decade in humans. The osteoclast is a key cell in homeostatic bone remodeling, but excess osteoclast activity leads to bone pathology, including the highly prevalent disease osteoporosis. In rheumatoid arthritis, the inflammatory environment activates osteoclasts, resulting in bone erosions and generalized bone loss. While the signaling pathways, transcription factors and molecular machinery that govern osteoclast differentiation and resorptive activity have been studied intensively over the past two decades, much less is understood about the generation, migration and commitment of OC precursor cells (OCP). In this grant we seek to expand our understanding of OCP function and trafficking in homeostatic and inflammatory bone remodeling in vivo. We have recently identified a bone marrow CD11b-/lo Ly6Chi population with ex vivo osteoclast precursor (OCP) activity. The experiments we propose will establish whether bone marrow CD11b-/lo Ly6Chi OCP are multi-potent myeloid precursors or are restricted to the osteoclast lineage in vivo. Building on this we will determine if inflammation induces cell intrinsic changes in the OCP that alter its progenitor properties and examine the requirements for OCP to traffic to inflamed joints. To establish whether mouse models investigating OCP can be applied to understanding human OCP, we propose to define the human bone marrow osteoclast precursor. This grant will advance our basic understanding of the osteoclast lineage in mice and humans, and contribute to knowledge about skeletal remodeling and joint destruction in inflammatory arthritis. We anticipate our data will be directly applicable to understanding bone destruction in RA, osteoporosis and related inflammatory diseases.

Public Health Relevance

Destruction of bone is a major cause of disability in rheumatoid arthritis, osteoporosis and primary and metastatic bone cancer. Only one cell in the body is capable of destroying bone: the osteoclast. Currently, how this cell arises in these diseases is poorly understood. The proposed studies will examine how osteoclasts are generated in mice and humans, how they contribute to bone loss and joint destruction in inflammatory arthritis, and how we can apply that knowledge to rheumatoid arthritis, osteoporosis and related skeletal diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Chen, Faye H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Yan, Jing; Charles, Julia F (2017) Gut Microbiome and Bone: to Build, Destroy, or Both? Curr Osteoporos Rep 15:376-384
Charles, Julia F; Sury, Meera; Tsang, Kelly et al. (2017) Utility of quantitative micro-computed tomographic analysis in zebrafish to define gene function during skeletogenesis. Bone 101:162-171
Lee, Pui Y; Sykes, David B; Ameri, Sarah et al. (2017) The metabolic regulator mTORC1 controls terminal myeloid differentiation. Sci Immunol 2:
Urso, Katia; Charles, Julia F; Shull, Gary E et al. (2016) Anion Exchanger 2 Regulates Dectin-1-Dependent Phagocytosis and Killing of Candida albicans. PLoS One 11:e0158893
Yan, Jing; Herzog, Jeremy W; Tsang, Kelly et al. (2016) Gut microbiota induce IGF-1 and promote bone formation and growth. Proc Natl Acad Sci U S A 113:E7554-E7563
O'Brien, William; Fissel, Brian M; Maeda, Yukiko et al. (2016) RANK-Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis. Arthritis Rheumatol 68:2889-2900
Greenblatt, Matthew B; Park, Kwang Hwan; Oh, Hwanhee et al. (2015) CHMP5 controls bone turnover rates by dampening NF-?B activity in osteoclasts. J Exp Med 212:1283-301
Charles, Julia F; Ermann, Joerg; Aliprantis, Antonios O (2015) The intestinal microbiome and skeletal fitness: Connecting bugs and bones. Clin Immunol 159:163-9
Bell, Sean M; Blumstein, Jessica; Brose, Katja et al. (2014) Defining success in graduate school. Mol Biol Cell 25:1942-4
Charles, Julia F; Aliprantis, Antonios O (2014) Osteoclasts: more than 'bone eaters'. Trends Mol Med 20:449-59

Showing the most recent 10 out of 13 publications