Patients suffering from persistent knee joint pain typically have cartilage degeneration with structural and morphological changes in synovium, meniscus and subchondral bone at the damage knee joint region. Osteoarthritis is a leading cause of musculoskeletal-associated pain, psychological distress, impaired quality of life, and staggering socio-economic costs (estimated at $100 billion per year in the US alone). Currently, there is no effective treatment for this common affliction. Relief of knee joint pain is hampered because causative mechanisms (e.g., the pain source and affected cellular pathways) have not yet been established. To investigate the etiology of back pain and assess opportunities for possible clinical intervention, we will investigate specific signaling pathways leading to knee joit osteoarthritis and its symptom, knee pain by using representative tools: 1) established OA animal model model for facilitating behavioral pain assessments that allow us to investigate pain mechanisms, 2) genetically modified mice to understand pathophysiological nociceptive pathway evoked by knee osteoarthritis, and 3) investigation of peripheral (dorsal root ganglions) and central (spinal dorsal horn) responses by knee joint OA and roles of glial activation in chronic knee joint osteoarthritic pain. Our studies may uncover the nociceptive pathway that is impaired in OA condition, and may reveal that alleviation of OA pain at the spinal level is indeed beneficial to the joints by arresting progressive cartilage destruction through neurogenic attenuation. Successful completion of these studies will establish that effective controls of the PKC axis not only protects peripheral knee joint tissues from further degeneration, but also relieves its clinically debilitating symptom, pain, that profoundly impacts on the quality of life or a vast number of patients.

Public Health Relevance

This application provides a unique opportunity to study nociceptive pathway initiated by osteoarthritis by combining genetically modified mice and established translational animal models that are amenable to behavioral pain tests that have set the stage for rapid advances in this highly under-studied area. Our results will discover a novel nociceptive pathway and molecular mechanisms that cannot be addressed by clinical protocols in humans, and will establish new experimental avenues and novel research directions for osteoarthritis-caused knee joint pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
4R01AR062136-05
Application #
9068662
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2012-07-01
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Zheng, Yixin; Liu, Cunchang; Ni, Li et al. (2018) Cell type-specific effects of Notch signaling activation on intervertebral discs: Implications for intervertebral disc degeneration. J Cell Physiol 233:5431-5440
Shi, Changgui; Qiu, Sujun; Riester, Scott M et al. (2018) Animal models for studying the etiology and treatment of low back pain. J Orthop Res 36:1305-1312
Chen, Di; Xie, Rong; Shu, Bing et al. (2018) Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging. Ann N Y Acad Sci :
Liao, Lifan; Zhang, Shanxing; Gu, Jianhong et al. (2017) Deletion of Runx2 in Articular Chondrocytes Decelerates the Progression of DMM-Induced Osteoarthritis in Adult Mice. Sci Rep 7:2371
Zhou, Yachuan; Wang, Tingyu; Hamilton, John L et al. (2017) Wnt/?-catenin Signaling in Osteoarthritis and in Other Forms of Arthritis. Curr Rheumatol Rep 19:53
Nagao, Masashi; Hamilton, John L; Kc, Ranjan et al. (2017) Vascular Endothelial Growth Factor in Cartilage Development and Osteoarthritis. Sci Rep 7:13027
Oh, Chun-do; Im, Hee-Jeong; Suh, Joon et al. (2016) Rho-Associated Kinase Inhibitor Immortalizes Rat Nucleus Pulposus and Annulus Fibrosus Cells: Establishment of Intervertebral Disc Cell Lines With Novel Approaches. Spine (Phila Pa 1976) 41:E255-61
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

Showing the most recent 10 out of 46 publications