There is an urgent need for new therapeutic agents that treat the pain associated with osteoarthritis (OA). OA is a chronic disease, and as disease progresses, patients can describe different types of pain, including pain on weightbearing or joint movement, and pain at rest. Some patients display signs of peripheral and/or central sensitization. Compelling clinical evidence suggests that ongoing peripheral input from the OA joint drives pain and sensitization. We have developed the murine DMM (destabilization of the medial meniscus) model to study the chronic nature of the disease and the different pain behaviors associated with progressive joint damage. The overarching aim is to characterize anatomical and functional alterations in the sensory innervation of the joint. We have uncovered that in the course of experimental OA, NaV1.8 nociceptors undergo profound, and previously unappreciated, plasticity at all levels (in the knee joint, in the DRG, and in the dorsal horn) in a precisely evolving manner. Recently, it has become clear that sensory neurons can be classified based on unique patterns of expression of molecules that underlie different aspects of somatic sensation. Specifically, NaV1.8 neurons comprise distinct functional subsets, including heat-sensitive TRPV1 neurons, mechanosensitive Mrgprd C-fibers, TH+ C-low threshold mechanoreceptors (C-LTMR), and silent CHRNA3 fibers. Another subset of potential relevance to OA pain is TrkA+, expressing the receptor for Nerve Growth Factor. We hypothesize that specific temporospatial changes in these subpopulations mediate the evolution of pain behaviors during OA progression. Our experimental plan considers two complementary aims to study (1) temporal and spatial contributions (which nerves are present and functional in the OA joint, where and when?); and (2) how we may target these specific neuronal subsets to examine effects on pain behaviors and joint health.
Specific Aim 1 aims to define temporal and spatial neuroplasticity of knee innervation in the context of OA joint pathology and pain. We have used a variety of Cre/Flp drivers to produce lines of fluorescent reporter mice specific for distinct subsets of nociceptive, mechanosensitive, and proprioceptive (parvalbumin, PV) DRG neurons. We will use these mice to define anatomical and functional changes in knee innervation, using confocal and lightsheet microscopy, in vivo Ca2+ imaging, and transient chemogenetic silencing of specific neuronal subsets.
Specific Aim 2 aims to target specific neuronal subsets and examine the effect on OA disease (pain and joint damage), in order to explore how our findings may translate to new approaches for OA pain. We will determine the effects of chronic chemogenetic silencing of neuronal subpopulations on OA pain and joint damage. We will also study the ?receptome? specific to DRG subpopulations in order to develop targeted therapeutic interventions. We propose that the identification of neuronal subpopulations that mediate OA pain behaviors will allow them to be specifically targeted at specific stages of the disease and this will result in novel, more efficacious and safer therapeutic approaches to OA pain.
Pain is the predominant reason why osteoarthritis patients seek medical help, but pathways of pain generation and maintenance are poorly understood. We use anatomical and functional neurobiological techniques to document, identify, and manipulate sensory afferents in the knee joint, with the aim to precisely define which neuronal subpopulations contribute to the different pain behaviors associated with progressive experimental osteoarthritis. This will aid in the development of safer and more efficacious analgesic therapies.
|Syx, Delfien; Tran, Phuong B; Miller, Rachel E et al. (2018) Peripheral Mechanisms Contributing to Osteoarthritis Pain. Curr Rheumatol Rep 20:9|
|Jayaraj, Nirupa D; Bhattacharyya, Bula J; Belmadani, Abdelhak A et al. (2018) Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy. J Clin Invest 128:2205-2225|
|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|
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