Bone loss is associated with a variety of conditions in which increased production of pro-inflammatory cytokines promotes bone loss by increasing osteoclast formation, activation and survival. Most published data indicate that these effects are mediated mainly indirectly through stromal cell production of M-CSF and RANKL, which bind to their receptors on osteoclasts and activate c-Fos/AP-1, NFkappaB, and NFAT2, expression of each of which is required for osteoclast formation. However, osteoclasts express receptors for a growing list of agents, including pro-inflammatory cytokines, suggesting that direct and indirect effects of cytokines on osteoclasts could combine to induce bone loss. Our over-riding hypothesis is that in disease states, osteoclast numbers may be regulated by direct effects of cytokines on cells in the osteoclast lineage that can lead to self perpetuating, up-regulatory cycles within these cells and subsequently to bone loss. However, the precise mechanisms and the signaling molecules involved remain to be fully elucidated. We plan to investigate the direct effects of cytokines on osteoclasts and their precursors and to determine the roles of c-Fos/AP-1, NFkappaB and NFAT2 signaling in this process using NFkappaB dKO, TNF transgenic and wild-type mice. We propose the following Specific Aims: 1. To fully characterize the effects of cytokines and retroviral transfer of c-Fos/AP-1 genes to wt and NFkB dKO splenocytes and to determine if other osteoclast stimulating factors induce osteoclast formation directly when c-Fos is expressed; 2. To determine the mechanisms whereby retroviral transfer of c-Fos and cytokines induce osteoclast formation directly and to examine the role of NFkB in this process; 3. To examine if cytokine and c-Fos/AP-1 expression are up-regulated in osteoclasts and their precursors in models of cytokine-mediated bone disease. These studies will better define the roles of key signaling pathways and advance our understanding of the mechanisms that directly regulate osteoclast formation and survival. Ultimately they should lead to the development of specific therapeutic agents to prevent and treat common bone diseases associated with increased osteoclast activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043510-13
Application #
7371980
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Sharrock, William J
Project Start
1995-06-01
Project End
2009-02-16
Budget Start
2008-02-01
Budget End
2009-02-16
Support Year
13
Fiscal Year
2008
Total Cost
$289,776
Indirect Cost
Name
University of Rochester
Department
Pathology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Boyce, Brendan F; Li, Jinbo; Xing, Lianping et al. (2018) Bone Remodeling and the Role of TRAF3 in Osteoclastic Bone Resorption. Front Immunol 9:2263
Xiu, Yan; Dong, Qianze; Li, Qingchang et al. (2018) Stabilization of NF-?B-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia. Cell Rep 22:350-358
Sun, Wen; Meednu, Nida; Rosenberg, Alexander et al. (2018) B cells inhibit bone formation in rheumatoid arthritis by suppressing osteoblast differentiation. Nat Commun 9:5127
Yao, Zhenqiang; Lei, Wei; Duan, Rong et al. (2017) RANKL cytokine enhances TNF-induced osteoclastogenesis independently of TNF receptor associated factor (TRAF) 6 by degrading TRAF3 in osteoclast precursors. J Biol Chem 292:10169-10179
Li, Xing; Sun, Wen; Li, Jinbo et al. (2017) Clomipramine causes osteoporosis by promoting osteoclastogenesis via E3 ligase Itch, which is prevented by Zoledronic acid. Sci Rep 7:41358
Wang, Wensheng; Wang, Hua; Zhou, Xichao et al. (2017) Lymphatic Endothelial Cells Produce M-CSF, Causing Massive Bone Loss in Mice. J Bone Miner Res 32:939-950
Sun, Wen; Zhang, Hengwei; Wang, Hua et al. (2017) Targeting Notch-Activated M1 Macrophages Attenuates Joint Tissue Damage in a Mouse Model of Inflammatory Arthritis. J Bone Miner Res 32:1469-1480
Zhang, Longze; Chang, Martin; Beck, Christopher A et al. (2016) Analysis of new bone, cartilage, and fibrosis tissue in healing murine allografts using whole slide imaging and a new automated histomorphometric algorithm. Bone Res 4:15037
Krieger, Nancy S; Yao, Zhenqiang; Kyker-Snowman, Kelly et al. (2016) Increased bone density in mice lacking the proton receptor OGR1. Kidney Int 89:565-73
Liang, Qianqian; Ju, Yawen; Chen, Yan et al. (2016) Lymphatic endothelial cells efferent to inflamed joints produce iNOS and inhibit lymphatic vessel contraction and drainage in TNF-induced arthritis in mice. Arthritis Res Ther 18:62

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