Osteoclasts are essential for bone modeling and remodeling and mediate bone loss in common bone diseases, including rheumatoid arthritis and postmenopausal osteoporosis, in which levels of proinflammatory cytokines, such as TNF, are increased and drive osteoclast formation both directly and indirectly through RANKL and three sets of transcription factors: NF-?B;c-Fos;and NFATc1. Expression of these is essential for osteoclast formation. RANKL/RANK signals through a canonical NF-?B1/p65 and an alternative NF-?B2/RelB pathway. To-date, most studies of NF-?B in osteoclasts have focused on the canonical pathway, and much less is known about the functional roles of NF-?B2 and RelB in regulating osteoclasts and other bone cells. Recently, we found that TNF induces NF-?B2 expression and that deletion of NF-?B2 increases TNF-induced osteoclast formation. TNF transgenic/NF-?B2-/- mice develop earlier and more severe joint erosion and inflammation and systemic bone loss than TNF-Tg mice. Furthermore, we found that RelB null mice have mild osteopetrosis. These findings highlight the importance of the alternative pathway in bone and suggest a new role for TNF to limit RANKL-induced bone loss in addition to its known role to stimulate osteoclast formation. Based on our preliminary data, we hypothesize that TNF can induce NF-?B2 expression to limit osteoclast formation stimulated by RANKL and that manipulation of NF-?B2/RelB expression will directly affect osteoclast functions. This hypothesis will be tested in the following 3 Specific Aims.
In Aim 1, we will determine if NF-?B2 limits OC formation by controlling signaling in both the canonical and alternative NF-?B pathways.
In Aim 2, we will determine the roles of NF-?B2 and RelB in osteoclast formation and activity.
In Aim 3, we will determine the effects of over-expression of NF-?B2p100 on TNF-induced bone loss. Our proposed studies should define the roles of NF-?B2 and RelB in osteoclast formation and activity and provide proof of concept that they are strong candidates for novel therapeutic intervention to limit cytokine-stimulated bone loss.

Public Health Relevance

Osteoclasts are the cells that degrade bone and over-activity of them causes bone loss in common diseases, such as rheumatoid arthritis. Our proposed studies, using animal models of these diseases, should lead to a better understanding of how osteoclast activity is regulated and eventually to the development of a novel therapy to limit this activity in these bone disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043510-18
Application #
8434078
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Chen, Faye H
Project Start
1995-06-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
18
Fiscal Year
2013
Total Cost
$313,864
Indirect Cost
$110,716
Name
University of Rochester
Department
Pathology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Xing, Lianping; Boyce, Brendan F (2014) RANKL-based osteoclastogenic assays from murine bone marrow cells. Methods Mol Biol 1130:307-13
Shi, Jixiang; Liang, Qianqian; Zuscik, Michael et al. (2014) Distribution and alteration of lymphatic vessels in knee joints of normal and osteoarthritic mice. Arthritis Rheumatol 66:657-66
Xiu, Yan; Xu, Hao; Zhao, Chen et al. (2014) Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation. J Clin Invest 124:297-310
Zhang, Hengwei; Hilton, Matthew J; Anolik, Jennifer H et al. (2014) NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-?B. J Clin Invest 124:3200-14
Yao, Zhenqiang; Li, Yanyun; Yin, Xiaoxiang et al. (2014) NF-?B RelB negatively regulates osteoblast differentiation and bone formation. J Bone Miner Res 29:866-77
Shu, Lei; Zhang, Hengwei; Boyce, Brendan F et al. (2013) Ubiquitin E3 ligase Wwp1 negatively regulates osteoblast function by inhibiting osteoblast differentiation and migration. J Bone Miner Res 28:1925-35
Zhang, Hengwei; Wu, Chengwu; Matesic, Lydia E et al. (2013) Ubiquitin E3 ligase Itch negatively regulates osteoclast formation by promoting deubiquitination of tumor necrosis factor (TNF) receptor-associated factor 6. J Biol Chem 288:22359-68
Boyce, B F (2013) Advances in the regulation of osteoclasts and osteoclast functions. J Dent Res 92:860-7
Boyce, Brendan F (2013) Advances in osteoclast biology reveal potential new drug targets and new roles for osteoclasts. J Bone Miner Res 28:711-22
Zhao, Chen; Xiu, Yan; Ashton, John et al. (2012) Noncanonical NF-ýýB signaling regulates hematopoietic stem cell self-renewal and microenvironment interactions. Stem Cells 30:709-18

Showing the most recent 10 out of 58 publications