Abstract

Tumor necrosis factor alpha (TNF-alpha) is an inflammatory cytokine with osteoclastogenic and osteolytic activities that contribute to pathogenesis of bone disorders such as periodontal disease, post-menopausal osteoporosis, and arthritis. This proposal will investigate mechanisms underlying TNF-alpha stimulation of osteoclast formation from mouse bone marrow macrophages (BMM). Proposed studies are based on the premise that two TNF-alpha receptors transduce TNF-alpha signals in osteoclast precursors with opposing effects on osteoclast formation. The p55 receptor (p55r) is proposed to mediate positive effects of TNF-alpha (mainly soluble TNF-alpha) on osteoclast formation through activation of c-src kinase, subsequent phosphorylation and inactivation of the NFkB inhibitor IkBalpha, and activation of NFkB. The p75 receptor (p75r) is proposed to mediate inhibitory effects of TNF-alpha (mainly membrane TNF-alpha) on osteoclast formation. This hypothesis is supported by previous studies and preliminary data.
The specific aims of the proposal are (1) to determine the mechanisms by which p55r promotes osteoclastogenesis, and (2) to determine the mechanisms by which p75r suppresses osteoclastogenesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013754-02
Application #
6175929
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1999-09-01
Project End
2004-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$207,840
Indirect Cost

  Institution

Name
Washington University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Abu-Amer, Yousef; Darwech, Isra; Clohisy, John C (2007) Aseptic loosening of total joint replacements: mechanisms underlying osteolysis and potential therapies. Arthritis Res Ther 9 Suppl 1:S6
Hirayama, Teruhisa; Dai, Simon; Abbas, Sabiha et al. (2005) Inhibition of inflammatory bone erosion by constitutively active STAT-6 through blockade of JNK and NF-kappaB activation. Arthritis Rheum 52:2719-29
Abu-Amer, Yousef (2005) Advances in osteoclast differentiation and function. Curr Drug Targets Immune Endocr Metabol Disord 5:347-55
Dai, Simon; Hirayama, Teruhisa; Abbas, Sabiha et al. (2004) The IkappaB kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks osteoclastogenesis and bone erosion in inflammatory arthritis. J Biol Chem 279:37219-22
Clohisy, John C; Hirayama, Teruhisa; Frazier, Elfaridah et al. (2004) NF-kB signaling blockade abolishes implant particle-induced osteoclastogenesis. J Orthop Res 22:13-20
Abu-Amer, Yousef; Abbas, Sabiha; Hirayama, Teruhisa (2004) TNF receptor type 1 regulates RANK ligand expression by stromal cells and modulates osteoclastogenesis. J Cell Biochem 93:980-9
Clohisy, John C; Roy, Bhabesh C; Biondo, Christine et al. (2003) Direct inhibition of NF-kappa B blocks bone erosion associated with inflammatory arthritis. J Immunol 171:5547-53
Abbas, Sabiha; Abu-Amer, Yousef (2003) Dominant-negative IkappaB facilitates apoptosis of osteoclasts by tumor necrosis factor-alpha. J Biol Chem 278:20077-82
Abbas, Sabiha; Zhang, Yan-Hong; Clohisy, John C et al. (2003) Tumor necrosis factor-alpha inhibits pre-osteoblast differentiation through its type-1 receptor. Cytokine 22:33-41
Clohisy, John C; Frazier, Elfaridah; Hirayama, Teruhisa et al. (2003) RANKL is an essential cytokine mediator of polymethylmethacrylate particle-induced osteoclastogenesis. J Orthop Res 21:202-12

Showing the most recent 10 out of 17 publications