Pain in osteoarthritis (OA) represents a major unmet medical need. Our understanding of the pathways that generate and maintain pain in OA remains poor. Cumulative data suggest that OA pain is generated through local mechanisms in the joint, while sensitization of the peripheral and central nervous system amplifies the pain and contributes to its chronicity. Destabilization of the medial meniscus (DMM) in wild-type C57BL/6 mice provides an in vivo model where joint pathology progresses slowly over 16 weeks, thus enabling the study of temporal changes in pain sensation in association with progressive joint pathology. We have generated compelling data that DMM-associated pain behavior presents in two stages: mechanical allodynia begins early, progresses up to 4 weeks, and is maintained for 16 weeks after surgery;stage two begins at week 8, with changes indicative of persistent pain, including decreased locomotion (distance traveled, climbing). Analysis of molecular changes in the innervating dorsal root ganglia (DRG) shows that monocyte chemoattractant protein 1 (MCP-1) and its high affinity receptor, CCR2, are highly upregulated in the DRG 8 weeks post DMM. Ccr2 null mice initially develop mechanical allodynia, but it begins to resolve 8 weeks post DMM. Pain behaviors indicative of persistent pain (decreased locomotion) do not occur in these mice, and they are partially protected from joint destruction by 16 weeks post DMM. Therefore, the goal of this proposal is to test the Central Hypothesis: MCP-1/CCR2 activity is a key driver for the maintenance of pain and structural damage in the DMM model.
Aim 1 seeks to determine the function of MCP-1/CCR2 in establishing chronic OA pain and joint pathology post DMM.
Aim 1 a will identify expression of MCP-1 and CCR2 by neurons, glia, and macrophages in the DRG and will examine downstream functional effects.
Aim 1 b will compare the progression of pathology, cellular infiltration, and cytokine expression in the knee joint of WT and Ccr2 null mice after DMM.
Aim 2 seeks to test the hypothesis that CCR2 blockade reduces pain behavior following DMM surgery.
This aim will test the ability of a CCR2 receptor antagonist to 1) Have an immediate analgesic effect on mechanical allodynia, and 2) Have disease-modifying effects on persistent OA pain behaviors and joint pathology by long-term intervention beginning at early or late stages of OA. Effects on pain behavior will be quantified on a bi-weekly basis by the following established measures (mechanical allodynia and locomotion);Effects on joint damage will be analyzed by histopathology.

Public Health Relevance

The pain that accompanies osteoarthritis represents a major unmet medical need. Better understanding the cellular and molecular mechanisms that lead to pain in osteoarthritis will have a major impact on treatments for pain relief, with potential applications to other musculoskeletal pain.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10B-S (20))
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Tyree, Bernadette
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Rush University Medical Center
Internal Medicine/Medicine
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United States
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Miller, Rachel E; Kim, Yu Shin; Tran, Phuong B et al. (2018) Visualization of Peripheral Neuron Sensitization in a Surgical Mouse Model of Osteoarthritis by In Vivo Calcium Imaging. Arthritis Rheumatol 70:88-97
Tran, P B; Miller, R E; Ishihara, S et al. (2017) Spinal microglial activation in a murine surgical model of knee osteoarthritis. Osteoarthritis Cartilage 25:718-726
Miotla Zarebska, J; Chanalaris, A; Driscoll, C et al. (2017) CCL2 and CCR2 regulate pain-related behaviour and early gene expression in post-traumatic murine osteoarthritis but contribute little to chondropathy. Osteoarthritis Cartilage 25:406-412
Miller, Rachel E; Ishihara, Shingo; Bhattacharyya, Bula et al. (2017) Chemogenetic Inhibition of Pain Neurons in a Mouse Model of Osteoarthritis. Arthritis Rheumatol 69:1429-1439
Miller, R E; Tran, P B; Ishihara, S et al. (2016) Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis. Osteoarthritis Cartilage 24:299-306
Miller, Rachel E; Belmadani, Abdelhak; Ishihara, Shingo et al. (2015) Damage-associated molecular patterns generated in osteoarthritis directly excite murine nociceptive neurons through Toll-like receptor 4. Arthritis Rheumatol 67:2933-43
Miller, Rachel E; Tran, Phuong B; Obeidat, Alia M et al. (2015) The Role of Peripheral Nociceptive Neurons in the Pathophysiology of Osteoarthritis Pain. Curr Osteoporos Rep 13:318-26
Larkin, J; Lohr, T A; Elefante, L et al. (2015) Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification. Osteoarthritis Cartilage 23:1254-66
Miller, Rachel E; Miller, Richard J; Malfait, Anne-Marie (2014) Osteoarthritis joint pain: the cytokine connection. Cytokine 70:185-93
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