Pain is the major symptom in osteoarthritis (OA) and one of the leading causes of impaired mobility in the elderly population in the US. Our lack of understanding of the mechanisms underlying chronic pain in general, and chronic pain associated with OA in particular, accounts for the general ineffectiveness of currently available treatment options. Relief from severe OA pain remains an unmet medical need and a major reason for seeking surgical intervention. The long-term goal of this proposal is to define origins and mechanisms of pain in OA, thus enabling identification of new targets, and development of new therapies and biomarkers for OA pain. Using a sophisticated chronic progressive murine model of knee OA, in combination with state-of-the-art approaches and potent, selective inhibitors, this proposal aims to systematically address the central hypothesis: pathological matrix turnover in the OA joint chronically activates joint nociceptors and causes plasticity changes in the nervous system, resulting in the initiation and the persistence of pain.
Aim 1 seeks to define a temporo-spatial role for the chemokines, MCP-1 and fractalkine, in chronic OA pain through longitudinal analysis of changes in the innervating DRG (peripheral nervous system) and dorsal horn (central nervous system) during the course of progressive experimental OA. In order to gain insight into OA pain modulation in the DRG (peripheral nervous system) and transition to the central nervous system, we aim to document molecular markers of activation of cellular subsets in DRG and DH in a temporo-spatial manner over the course of progressive OA. Further, we will test the effect of interfering with MCP-1/CCR2 signaling on pain behaviors and associated pathways.
Aim 2 seeks to evaluate the contribution of Pattern Recognition Receptors (PRR) and their ligands (Damage Associated Molecular Patterns, DAMPs) to joint nociceptor activation and OA-associated pain. We will visualize TLR2/4 and RAGE expression on joint nociceptors in the course of progressive knee OA after DMM surgery, using novel Nav1.8-tdTomato reporter mice. We will evaluate the ability of selected DAMPs to activate sensory neurons, using intracellular Ca2+ mobilization and MCP-1 release as outcome markers. In order to assess the contribution of DAMP signaling to pain in this model, we will evaluate pain-related behaviors in novel conditional knock-out mice that lack Myd88 or TLR4 in pain-sensing neurons. Finally, Aim 3 seeks to differentially target pathological components of the OA joint in order to assess effects on pain and associated pathways.
We aim to differentially target cartilage or subchondral bone through pharmacological modulation at different times during progressive disease, and monitor pain/pain pathway outcome markers in association with detailed joint histopathology. This will clarify sources and regulation of OA pain in the joint.
These aims will lead to considerable gains in understanding how pain is in generated and maintained in OA, and pave the way for a more targeted and safer therapeutic approach.

Public Health Relevance

Osteoarthritis (OA) pain represents a major unmet medical need. A better understanding of the molecular mechanisms that trigger and maintain OA pain and clearer insight into the relationship between pain pathways and structural changes in joint tissues will have a major impact on development of OA treatments.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01AR060364-04A1
Application #
8817111
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Malfait, A M; Little, C B; McDougall, J J (2013) A commentary on modelling osteoarthritis pain in small animals. Osteoarthritis Cartilage 21:1316-26
Malfait, Anne-Marie; Schnitzer, Thomas J (2013) Towards a mechanism-based approach to pain management in osteoarthritis. Nat Rev Rheumatol 9:654-64
Miller, Rachel E; Lu, Yongzhi; Tortorella, Micky D et al. (2013) Genetically Engineered Mouse Models Reveal the Importance of Proteases as Osteoarthritis Drug Targets. Curr Rheumatol Rep 15:350
Malfait, Anne-Marie; Seymour, Albert B; Gao, Feng et al. (2012) A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype. Ann Rheum Dis 71:1042-8