EXCEED THE SPACE PROVIDED. Inflammatory osteolysis, as in rheumatoid arthritis (RA), reflects increased osteoclast (OC) activity. OC recruitment is mediated via RANKL interaction with its receptor, RANK. We and others have established that TNF plays a key role in the pathogenesis of inflammatory osteolysis and other forms of inflammation-induced bone loss. Central to this proposal are our observations that RANKL and TNF both activate Nf-kB and AP-1/cJun signaling pathways, and TNF dramatically stimulates RANKL-induced osteoclastogenesis via TNFrl. Reduced osteoclastogenesis correlates with diminished NF-kB and c-Jun activation by TNF and RANKL in TNFrl-/- cells. These facts, together with our findings that RANKL and TNF stimulate recruitment of TRAF2 and TRAF6 to their receptors, points to a possible intracellular coupling between these two receptors which in turn leads to a super osteoclastic response. Supporting this hypothesis is the fact that RANK utilizes the traditional TNFr-recruiting machinery to activate NF-kB and c-Jun signaling pathways. Taken together, our data point that enhanced osteoclastogenesis (as in inflammatory osteolysis) requires the presence of TNFRl. Therefore, understanding the exact mechanisms by which TNF promotes RANKL-dependent osteoclastogenesis and thus, inflammatory osteopenia, may provide a foundation for developing osteoclast inhibitory strategies. Molecular inhibition of osteoclastogenesis by anti-inflammatory cytokines is under-investigated. IL-4,the major soluble factor secreted by T helper-2 (TH2) lymphocytes, is an anti-inflammatory cytokine and a potent inhibitor of osteoclast differentiation. However, its anti-osteoclastic mechanism is unknown. We provide evidence that IL-4 blocks RANKL-induced NF-kB activation in osteoclast precursors. More importantly, using STAT6-/- cells we find that inhibition of NF-kB activation and osteoclastogenesis by IL-4 is a STAT6-dependent event. Given the inflammatory and osteoclastogenic role of NF-kB and that STAT proteins can act as transcriptional inhibitors, our observations raise the possibility that IL-4exerts its anti-osteoclastogenic effects via inhibition of RANKL activation of NF-kB and perhaps AP-1 signaling pathways. Understanding the molecular steps of IL-4/STAT6-inhibition of osteoclastogenesis, may provide the foundation for controlling inflammatory osteolysis.
Our Specific Aims are to determine: 1) the mechanism(s) by which TNFrl signaling pathway stimulates RANKL-mediated osteoclastogenesis, 2) the mechanism(s) by which IL-4 inhibits RANKL-mediated osteoclastogenesis. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047443-04
Application #
6944902
Study Section
Special Emphasis Panel (ZRG1-OBM-2 (01))
Program Officer
Gretz, Elizabeth
Project Start
2002-09-01
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2007-08-31
Support Year
4
Fiscal Year
2005
Total Cost
$219,555
Indirect Cost
Name
Washington University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Abu-Amer, Yousef (2009) Inflammation, cancer, and bone loss. Curr Opin Pharmacol 9:427-33
Yamanaka, Yasuhiro; Abu-Amer, Wahid; Foglia, Dominica et al. (2008) NFAT2 is an essential mediator of orthopedic particle-induced osteoclastogenesis. J Orthop Res 26:1577-84
Abu-Amer, Yousef; Darwech, Isra; Otero, Jesse (2008) Role of the NF-kappaB axis in immune modulation of osteoclasts and bone loss. Autoimmunity 41:204-11
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
Yamanaka, Y; Abu-Amer, Y; Faccio, R et al. (2006) Map kinase c-JUN N-terminal kinase mediates PMMA induction of osteoclasts. J Orthop Res 24:1349-57
Clohisy, John C; Yamanaka, Yasuhiro; Faccio, Roberta et al. (2006) Inhibition of IKK activation, through sequestering NEMO, blocks PMMA-induced osteoclastogenesis and calvarial inflammatory osteolysis. J Orthop Res 24:1358-65
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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

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