Osteoarthritis (OA), commonly referred as arthritis, causing painful joints, is among the most common chronic conditions among veterans. Indeed, the condition is much worse among veterans than non-veterans; one of every four veterans lives with a serious arthritic condition and individuals over age 40 are twice as likely to develop arthritis after returning to civilian life. Osteoarthritic symptom, pain, is the key reason to seek medical assistance, yet there is no effective way to relieve OA-induced pain. Despite the major negative impact that severe pain in chronic OA has on quality of life and health care management, we only poorly understand origins of pain in OA, the molecular mechanisms driving the pathology, and the way to effectively cure OA. Many cases eventually require joint replacement with a prosthesis which is costly, and the limited functional life of prostheses (~10 y) can make a second replacement necessary. These factors increase both the overall cost of treatment and the risk for associated morbidity. Significantly, surgical procedures to address the condition typically do not result in a pain-free cure. Our central hypothesis is that activation of Flt1 (vascular endothelial growth factor receptor-1) is the major driver of joint pain transmission by plasticity of peripheral (sensory neurons) and central glial activation; Flk1 (vascular endothelial growth factor receptor-2) is primarily responsible for cartilage degeneration during the OA progression, thus, simultaneous inhibition of Flt1 and Flk1 by pazopanib, an FDA-approved small molecule anti-cancer drug, will act as an ideal OA disease-modifying drug (OADMD) with immediate reduction of joint pain and gradually cartilage regeneration. The findings of our proposed research will take the field of OA research a giant step forward: in the short term, by increasing our mechanistic understanding of the causes and progression of OA, and by developing a novel strategy for treating OA and joint pain effectively and safely in our pre-clinical OA animal model; and, in the longer term, by providing a rationale for clinical trials to test pazopanib to treat OA patients.

Public Health Relevance

This application provides a unique opportunity to study nociceptive pathway initiated by osteoarthritis by combining genetically modified mice and an established translational animal model that are amenable to behavioral pain tests that have set the stage for rapid advances in this highly under-studied area. We will evaluate pazopanib, an FDA-approved small molecule anti-cancer drug that inhibits VEGFRs, as an ideal OA disease-modifying drug (OADMD) that will elicit multiple effects simultaneously: (i) rapid joint pain reduction; (ii) inhibition of cartilage degeneration that gradually allows cartilage regeneration, and to understand how pazopanib works by determining its molecular and cellular mechanisms. Our findings will provide essential information that leads to studies using a larger animal model and will be rapidly translatable to clinical settings. PHS 398 (Rev. 11/07) Page 1 Continuation Format Page

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRD1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Jesse Brown VA Medical Center
United States
Zip Code
Chen, Di; Shen, Jie; Zhao, Weiwei et al. (2017) Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res 5:16044
Nagao, Masashi; Hamilton, John L; Kc, Ranjan et al. (2017) Vascular Endothelial Growth Factor in Cartilage Development and Osteoarthritis. Sci Rep 7:13027
Im, Hee-Jin; Baek, Shin-Hye; Chu, Min Kyung et al. (2017) Association Between Weekend Catch-up Sleep and Lower Body Mass: Population-Based Study. Sleep 40:
Im, Hyung-Jun; Hahm, Jarang; Kang, Hyejin et al. (2016) Disrupted brain metabolic connectivity in a 6-OHDA-induced mouse model of Parkinson's disease examined using persistent homology-based analysis. Sci Rep 6:33875
Lewallen, Eric A; Bonin, Carolina A; Li, Xin et al. (2016) The synovial microenvironment of osteoarthritic joints alters RNA-seq expression profiles of human primary articular chondrocytes. Gene 591:456-64
Kc, Ranjan; Li, Xin; Kroin, Jeffrey S et al. (2016) PKC? null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth. Ann Rheum Dis 75:2133-2141
Dudek, Michal; Gossan, Nicole; Yang, Nan et al. (2016) The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity. J Clin Invest 126:365-76
Im, Hwi-Jin; Kim, Hyeong-Geug; Lee, Jin-Seok et al. (2016) A Preclinical Model of Chronic Alcohol Consumption Reveals Increased Metastatic Seeding of Colon Cancer Cells in the Liver. Cancer Res 76:1698-704
Hamilton, John L; Nagao, Masashi; Levine, Brett R et al. (2016) Targeting VEGF and Its Receptors for the Treatment of Osteoarthritis and Associated Pain. J Bone Miner Res 31:911-24
Kroin, Jeffrey S; Kc, Ranjan; Li, Xin et al. (2016) Intraarticular slow-release triamcinolone acetate reduces allodynia in an experimental mouse knee osteoarthritis model. Gene 591:1-5

Showing the most recent 10 out of 61 publications