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.
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.
|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|
|Zhang, Hengwei; Sun, Wen; Li, Xing et al. (2016) Use of Hes1-GFP reporter mice to assess activity of the Hes1 promoter in bone cells under chronic inflammation. Bone 90:80-9|
|Boyce, Brendan F; Xiu, Yan; Li, Jinbo et al. (2015) NF-?B-Mediated Regulation of Osteoclastogenesis. Endocrinol Metab (Seoul) 30:35-44|
|Zhao, Zhijun; Hou, Xiaodong; Yin, Xiaoxiang et al. (2015) TNF Induction of NF-?B RelB Enhances RANKL-Induced Osteoclastogenesis by Promoting Inflammatory Macrophage Differentiation but also Limits It through Suppression of NFATc1 Expression. PLoS One 10:e0135728|
Showing the most recent 10 out of 77 publications