Bones provide rigid support for the body, maintain mineral homeostasis, and serve as the primary site for hematopoiesis. Bone homeostasis is maintained by the balanced action of osteoblasts and osteoclasts. Osteoclasts resorb bone and are derived from hematopoietic precursor cells. The formation and activation of osteoclasts are tightly regulated by osteoblasts, which provide two essential factors for osteoclastogenesis: TRANCE and M-CSF. Osteoblastic cells produce additional costimulators and inhibitory factors that further influence osteoblast-induced osteoclastogenesis. Many of the osteotropic factors modulating osteoclast differentiation exert their actions by regulating osteoblasts. This application stems in part from our attempt to provide insight into how osteotropic factors regulate osteoclast differentiation by modulating osteoblast activity. In our preliminary data, we have identified a member of the leucine rich repeat (LRR) proteins, LRRc17 (LRR containing 17), of previously unknown function, whose expression is highly enriched in osteoblasts. LRR motifs are found in various cytoplasmic, membrane and extracellular proteins (e.g., toll-like receptors). Although these proteins are associated with widely varied functions, a common property of LRR is involvement in protein-protein interaction. We show that LRRc17 mRNA expression in osteoblasts is suppressed in response to the pro-osteoclastogenic factor 1,25- dihydroxyvitamin D3 (1,25(OH)2D3), and enforced LRRc 17 expression in osteoblasts results in a failure of 1,25(OH)2D3 to induce osteoclast differentiation. These results strongly suggest that LRRc17 is an important negative regulator of osteoclast differentiation. Therefore, we propose to extend these studies of the regulation of osteoclast differentiation by LRRc17 by pursuing the following specific aims: (1) further characterization of the role of LRRc17 in osteoclast differentiation in vitro, (2) investigation of the role of LRRc17 as an inhibitor of bone resorption in vivo, and (3) investigation of the physiological role of LRRc17 in vivo. The knowledge gained from these studies will provide insights into how different molecules cooperate in inducing osteoclast differentiation, and how osteoclasts and osteoblasts communicate to regulate each other's function, which, in turn may help improve the treatment and prevention of osteoporosis and other bone diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR053843-02
Application #
7261415
Study Section
Special Emphasis Panel (ZRG1-MOSS-B (02))
Program Officer
Sharrock, William J
Project Start
2006-07-17
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$336,452
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ramos, Paula S; Oates, James C; Kamen, Diane L et al. (2013) Variable association of reactive intermediate genes with systemic lupus erythematosus in populations with different African ancestry. J Rheumatol 40:842-9
Kim, Jung Ha; Kim, Kabsun; Jin, Hye Mi et al. (2010) Negative feedback control of osteoclast formation through ubiquitin-mediated down-regulation of NFATc1. J Biol Chem 285:5224-31
Choi, Yongwon; Walsh, Matthew C; Arron, Joseph R (2009) Breaking into bone biology: target practice. Nat Med 15:144-5
Kim, Hyunsoo; Choi, Han Kyoung; Shin, Ji Hye et al. (2009) Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice. J Clin Invest 119:813-25
Kim, Taesoo; Kim, Kabsun; Lee, Seoung Hoon et al. (2009) Identification of LRRc17 as a negative regulator of receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast differentiation. J Biol Chem 284:15308-16
Zhao, Baohong; Takami, Masamichi; Yamada, Atsushi et al. (2009) Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis. Nat Med 15:1066-71
Lorenzo, Joseph; Horowitz, Mark; Choi, Yongwon (2008) Osteoimmunology: interactions of the bone and immune system. Endocr Rev 29:403-40