Both viral and genetic factors have been implicated in the pathogenesis of Paget's disease (PD). However, the molecular mechanisms responsible for their effect on osteoclast (OCL) formation and activity in PD are unclear. It is our hypothesis that measles virus nucleoprotein (MVNP) mediates its effects in OCL precursors predominantly through increased NFicB signaling via activation of the two kB kinase (IKK)-related kinases IKKe (also called IKK-/) and TANK-binding kinase 1 (TBK1) and increased levels of RIP1 and TRAF2. This results in upregulation of IL-6 and a vitamin D receptor coactivator TAFM-17 and increases OCL formation. MVNP also drives multi-potential cells towards the OCL lineage through increased expression and activation of NFATd. The p62P392L mutation linked to PD enhances the effects of MVNP by further increasing NFxB signaling in response to TNF-ct and RANKL as well as increasing p38 MAPK activation in response to RANKL, TNF-alpha and 1,25-(OH)2D3. In support of this hypothesis, we recently found that MVNP expression increases RIP1, TRAF2, and p65 NFicB resulting in enhanced constitutive activation of NFicB, and increased NFicB responsivity to TNF-alpha and RANKL. We also found that MVNP increases NFATd and synergistically activates NFATcl-driven gene transcription, with either NFATd 'or RANKL, and induces IL-6 and TAFn-17. In addition, the p62p392L mutation activates NFicB and increases the sensitivity of OCL precursors to RANKL and TNF-alpha. MVNP also interacts with IKKe and TBK1 to activate NFKB but their role in PD are unknown. In this project we will: 1. Determine if MVNP activation of NFKB and induction of pagetic OCL formation results from alterations of the canonical pathway and/or utilization of an alternative pathway that involves activation of IKKepsilon/TBK1 and the effects of co-expression of MVNP and p62P392L on these pathways. 2. Determine if NFKB activation by MVNP is sufficient for induction of IL-6 or if other mechanisms are also necessary, and the effects of co-expression of p62R392L and MVNP on the molecular mechanlsm(s) identified above. 3. Determine if the synergy of MVNP with NFATd is due to modulation of NFATd activation or of a cofactor of NFATd. The studies of the molecular mechanisms responsible for MVNP and p62p392L effects on OCL formation outlined above" will provide important insight into the pathogenesis of PD and are directly linked to the cellular and in vivo studies proposed in Project 2,

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR057310-05
Application #
8315745
Study Section
Special Emphasis Panel (ZAR1-MLB-G (M2))
Program Officer
Sharrock, William J
Project Start
2008-09-16
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$315,389
Indirect Cost
$84,514
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Sun, Quanhong; Sammut, Benedicte; Wang, Feng-Ming et al. (2014) TBK1 mediates critical effects of measles virus nucleocapsid protein (MVNP) on pagetic osteoclast formation. J Bone Miner Res 29:90-102
Galson, Deborah L; Roodman, G David (2014) Pathobiology of Paget's Disease of Bone. J Bone Metab 21:85-98
Teramachi, Jumpei; Zhou, Hua; Subler, Mark A et al. (2014) Increased IL-6 expression in osteoclasts is necessary but not sufficient for the development of Paget's disease of bone. J Bone Miner Res 29:1456-65
Teramachi, Jumpei; Hiruma, Yuko; Ishizuka, Seiichi et al. (2013) Role of ATF7-TAF12 interactions in the vitamin D response hypersensitivity of osteoclast precursors in Paget's disease. J Bone Miner Res 28:1489-500
Wang, Feng-Ming; Sarmasik, Aliye; Hiruma, Yuko et al. (2013) Measles virus nucleocapsid protein, a key contributor to Paget's disease, increases IL-6 expression via down-regulation of FoxO3/Sirt1 signaling. Bone 53:269-76
Adamik, Juraj; Wang, Kent Z Q; Unlu, Sebnem et al. (2013) Distinct mechanisms for induction and tolerance regulate the immediate early genes encoding interleukin 1* and tumor necrosis factor *. PLoS One 8:e70622
Zhu, Ke; Jiao, Hongli; Li, Shuai et al. (2013) ATF4 promotes bone angiogenesis by increasing VEGF expression and release in the bone environment. J Bone Miner Res 28:1870-84
Ishizuka, Hisako; Garcia-Palacios, Veronica; Lu, Ganwei et al. (2011) ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo. J Bone Miner Res 26:169-81
Kurihara, Noriyoshi; Hiruma, Yuko; Yamana, Kei et al. (2011) Contributions of the measles virus nucleocapsid gene and the SQSTM1/p62(P392L) mutation to Paget's disease. Cell Metab 13:23-34
Cao, Huiling; Yu, Shibing; Yao, Zhi et al. (2010) Activating transcription factor 4 regulates osteoclast differentiation in mice. J Clin Invest 120:2755-66

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