RANKL, also known as OPGL/ODF/TRANCE, is a member of the tumor necrosis factor (TNF) superfamily that plays an important role in osteoclast differentiation, function and survival. RANKL exerts these effects by binding to its receptor RANK, which is expressed on osteoclast precursors and mature osteoclasts. RANKL has been shown to activate six major signaling pathways: NF-kappa B, JNK, ERK, p38, NFATc1 and AKT. RANK belongs to the TNF receptor (TNFR) family and, hence, it transduces intracellular signals by recruiting various adaptor proteins including TNF receptor associated factors (TRAFs) through the specific motifs in the cytoplasmic domain. In the previous years of this grant we have characterized three TRAF-binding motifs that regulate osteoclast formation, function, and/or survival by activating one or more of the six known signaling pathways. Most importantly, however, we have also elucidated a 4-a.a. novel RANK cytoplasmic motif (IVVY535-538) that plays an essential role in osteoclastogenesis. This novel motif plays a crucial role in osteoclastogenesis by committing macrophages to the osteoclast lineage. Moreover, this RANK motif is NOT involved in the activation of the known RANK signaling pathways, indicating that it initiates a novel pathway(s). Based on these data, we hypothesize that, in addition to the known signaling pathways, RANK also activates an unidentified signaling pathway(s) critical for osteoclastogenesis through the novel motif. Thus, in the current application, we propose to identify and characterize the novel signaling pathways by investigating the following specific aims: 1) Investigate the functional relationship between the three TRAF-binding sites and the novel RANK motif; 2) Identify and characterize the downstream signaling protein that interacts with the novel RANK motif; 3) Investigate the role of the novel RANK motif in osteoclastogenesis in vivo by generating and characterizing knockin mice bearing an inactivating mutation in the novel RANK motif. The identification and characterization of the novel RANK signaling pathways will not only provide crucial insight into the molecular mechanism of osteoclastogenesis, but, more importantly, may lead to the development of more potent and specific therapeutics for various bone diseases including postmenopausal osteoporosis, boss loss in rheumatoid arthritis (RA) and tumor-induced osteolysis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047830-07
Application #
7270519
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
2001-04-01
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
7
Fiscal Year
2007
Total Cost
$332,385
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Jules, Joel; Chen, Wei; Feng, Xu et al. (2018) C/EBP? transcription factor is regulated by the RANK cytoplasmic 535IVVY538 motif and stimulates osteoclastogenesis more strongly than c-Fos. J Biol Chem 293:1480-1492
Jules, Joel; Wang, Shunqing; Shi, Zhenqi et al. (2015) The IVVY Motif and Tumor Necrosis Factor Receptor-associated Factor (TRAF) Sites in the Cytoplasmic Domain of the Receptor Activator of Nuclear Factor ?B (RANK) Cooperate to Induce Osteoclastogenesis. J Biol Chem 290:23738-50
Jules, Joel; Feng, Xu (2014) In vitro investigation of the roles of the proinflammatory cytokines tumor necrosis factor-? and interleukin-1 in murine osteoclastogenesis. Methods Mol Biol 1155:109-23
Zhao, Dongfeng; Shi, Zhenqi; Warriner, Amy H et al. (2014) Molecular mechanism of thiazolidinedione-mediated inhibitory effects on osteoclastogenesis. PLoS One 9:e102706
Hong, Huixian; Shi, Zhenqi; Qiao, Ping et al. (2013) Interleukin-3 plays dual roles in osteoclastogenesis by promoting the development of osteoclast progenitors but inhibiting the osteoclastogenic process. Biochem Biophys Res Commun 440:545-50
McCoy, Erin M; Hong, Huixian; Pruitt, Hawley C et al. (2013) IL-11 produced by breast cancer cells augments osteoclastogenesis by sustaining the pool of osteoclast progenitor cells. BMC Cancer 13:16
Izawa, Takashi; Zou, Wei; Chappel, Jean C et al. (2012) c-Src links a RANK/ýývýý3 integrin complex to the osteoclast cytoskeleton. Mol Cell Biol 32:2943-53
Jules, Joel; Zhang, Ping; Ashley, Jason W et al. (2012) Molecular basis of requirement of receptor activator of nuclear factor ?B signaling for interleukin 1-mediated osteoclastogenesis. J Biol Chem 287:15728-38
Cheng, Jing; Liu, Jianzhong; Shi, Zhenqi et al. (2011) Interleukin-4 inhibits RANKL-induced NFATc1 expression via STAT6: a novel mechanism mediating its blockade of osteoclastogenesis. J Cell Biochem 112:3385-92
Ashley, Jason W; Shi, Zhenqi; Zhao, Haibo et al. (2011) Genetic ablation of CD68 results in mice with increased bone and dysfunctional osteoclasts. PLoS One 6:e25838

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