Pain is the major symptom in osteoarthritis (OA), contributing to impaired function and loss of quality of life, and one of the leading causes of impaired mobility in the elderly population in the US. Our lack of understanding 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. In spite of its major impact on quality of life and health care management, our understanding of the mechanisms of pain in human OA remains very poor. 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. Compelling motivating data, along with novel genetically modified mice, have created a unique opportunity for immediate studies and rapid advances in this highly understudied area. The goal of these studies is three-fold: 1) Use a validated murine OA model, destabilization of the medial meniscus (DMM), to quantitatively measure pain and determine concurrent cellular and structural alterations in joint tissues and their sensory innervation (peripheral component and dorsal root ganglia). The goal is to make a qualitative and quantitative assessment of pain in the 16-week course of the disease using techniques that evaluate mechanical allodynia, spontaneous pain behavior and gait. A detailed correlation of pain measures will be made with pathological changes in all joint tissues (cartilage, bone, synovium, and meniscus) and with concomitant changes in the number and location of afferent neurites in the joint and dorsal root ganglia;2) Determine the effect of inhibiting ADAMTS-5 on pain detected in association with structural joint and neuronal changes in the DMM model. Inhibition will be achieved in vivo a) by using Adamts5 null mice and b) by pharmacological inhibition of ADAMTS-5 with potent and selective inhibitors. The absence of active ADAMTS-5 protects against OA progression in the DMM model. ADAMTS-5 inhibitors are being developed as disease-modifying OA drugs, without clear understanding of their potential to affect pain. These studies should allow us to determine whether these inhibitors will also affect pain, and how long after onset of disease the pain associated with OA structural changes is reversible or at what stage the pain has become irreversible. Findings here are expected to have important implications for pain management in human OA;3) Dissect molecular pathways participating in onset and chronicity of OA-related pain in the DMM model, through temporal analysis of molecular markers of nociceptive pathways, glial activation, and hyalectan fragments. Specifically, the temporal role of the NGF-mediated and the MCP-1-mediated nociceptor pathway will be explored. Genes implicated in these animal studies will provide the basis for genetic linkage analysis in large human OA cohorts with known pain and disability measures such as the WOMAC score.

Public Health Relevance

The pain that accompanies osteoarthritis represents a major unmet medical need. Understanding the cellular and molecular mechanisms that lead to chronic 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)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Tyree, Bernadette
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Rush University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Syx, Delfien; Tran, Phuong B; Miller, Rachel E et al. (2018) Peripheral Mechanisms Contributing to Osteoarthritis Pain. Curr Rheumatol Rep 20:9
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
Miller, Rachel E; Block, Joel A; Malfait, Anne-Marie (2018) What is new in pain modification in osteoarthritis? Rheumatology (Oxford) 57:iv99-iv107
Sambamurthy, Nisha; Nguyen, Vu; Smalley, Ryan et al. (2018) Chemokine receptor-7 (CCR7) deficiency leads to delayed development of joint damage and functional deficits in a murine model of osteoarthritis. J Orthop Res 36:864-875
Miller, Rachel E; Ishihara, Shingo; Tran, Phuong B et al. (2018) An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2. JCI Insight 3:
Miller, Rachel E; Malfait, Anne-Marie (2017) Osteoarthritis pain: What are we learning from animal models? Best Pract Res Clin Rheumatol 31:676-687
Miller, R E; Malfait, A-M (2017) Can we target CCR2 to treat osteoarthritis? The trick is in the timing! Osteoarthritis Cartilage 25:799-801
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
Miller, Rachel E; Block, Joel A; Malfait, Anne-Marie (2017) Nerve growth factor blockade for the management of osteoarthritis pain: what can we learn from clinical trials and preclinical models? Curr Opin Rheumatol 29:110-118
Malfait, Anne-Marie (2017) Why we should study pain in animal models of rheumatic diseases. Clin Exp Rheumatol 35 Suppl 107:37-39

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