The joints in arthritis are characterized by inflammatory cell infiltration, expansion of synovial cells and pannus formation, resulting in destruction of cartilage and bone. Angiogenesis plays a critical role in the pathogenesis of the disease. Neovascularization is required not only to maintain this tumor-like mass in the arthritic joint but also to play an active role in inflammation as a source of both cytokines and proteases and for inflammatory cell adhesion and infiltration. Therefore, activated endothelium in the inflammatory joint is a promising target for therapeutic intervention. Tie2 and VEGF receptor (VEGFR) are two endothelium- specific receptor tyrosine kinases. VEGFR and Tie2 work in a complementary and coordinated fashion to regulate vascular formation and function. It is also increasingly evident that these angiogenic factors also regulate inflammation and have effects that extend beyond these conventionally defined roles. VEGF/ VEGFR and Ang/Tie2 (Ang is the ligand forTie2) are elevated in patients and contribute to vascular inflammation, angiogenesis and arthritis progression. Recently, we found that neutralizing Tie2 function prevents bone from erosion in arthritis joints presumably via downregulation of RANKL. In addition, the expression of Ang/Tie2 and VEGFA/EGFR is coordinately induced in synoviocytes and endothelial cells (ECs) by TNF-alpha, a key cytokine in the inflammatory joint, illustrating an intimate interaction between these two cellular components. Based on these, we hypothesize that Tie2 and VEGFR signaling jointly regulates endothelial activation, EC-synoviocyte and EC-osteoclast interaction that lead to vascular inflammation, angiogenic response, bone erosion and disease development in arthritis joints. This proposed study will investigate the interaction and coordination of Ang/Tie2 and VEGFA/EGFR signals in these pathological processes.
Our specific aims are: 1). Investigate the interactive effects of Ang &VEGF in vascular inflammation, EC-osteoclast interaction and osteoclast maturation using in vitro co-culture assays;2) Examine the interactive effects of Ang &VEGF in leukocyte and osteoclast infiltration and maturation, angiogenesis and vascular survival using an in vivo synovium vascular window model;3) Identify the role of Tie2 and VEGFR signaling in synovial inflammation, angiogenesis, bone erosion and disease development using a chronic arthritis animal model coupled with novel non-invasive imaging approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR053718-05
Application #
7858341
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Mao, Su-Yau
Project Start
2006-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$318,136
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Ghose, Sampa; Min, Yongfen; Lin, P Charles (2015) ?-Catenin activates Rho GTPase, promotes lymphangiogenesis and growth of tumor metastases. PLoS One 10:e0116338
Min, Y; Ghose, S; Boelte, K et al. (2011) C/EBP-? regulates VEGF-C autocrine signaling in lymphangiogenesis and metastasis of lung cancer through HIF-1?. Oncogene 30:4901-9
Boelte, Kimberly C; Gordy, Laura E; Joyce, Sebastian et al. (2011) Rgs2 mediates pro-angiogenic function of myeloid derived suppressor cells in the tumor microenvironment via upregulation of MCP-1. PLoS One 6:e18534
Boutte, Angela M; Friedman, David B; Bogyo, Matthew et al. (2011) Identification of a myeloid-derived suppressor cell cystatin-like protein that inhibits metastasis. FASEB J 25:2626-37
Boutte, Angela M; McDonald, W Hayes; Shyr, Yu et al. (2011) Characterization of the MDSC proteome associated with metastatic murine mammary tumors using label-free mass spectrometry and shotgun proteomics. PLoS One 6:e22446
Min, Yongfen; Ren, Xiubao; Vaught, David B et al. (2010) Tie2 signaling regulates osteoclastogenesis and osteolytic bone invasion of breast cancer. Cancer Res 70:2819-28
DeBusk, Laura M; Boelte, Kimberly; Min, Yongfen et al. (2010) Heterozygous deficiency of delta-catenin impairs pathological angiogenesis. J Exp Med 207:77-84
Shaifer, Candice A; Huang, Jianhua; Lin, Pengnain Charles (2010) Glioblastoma cells incorporate into tumor vasculature and contribute to vascular radioresistance. Int J Cancer 127:2063-75
Kobayashi, Hanako; Huang, Jianhua; Ye, Fei et al. (2010) Interleukin-32beta propagates vascular inflammation and exacerbates sepsis in a mouse model. PLoS One 5:e9458
Kobayashi, Hanako; Lin, P Charles (2009) Molecular characterization of IL-32 in human endothelial cells. Cytokine 46:351-8

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