Determining the Functional Profile of Dorsal Root Ganglion Neurons Driving Osteoarthritis Pain

Osteoarthritis (OA) is a progressive joint disease that causes chronic pain, limiting mobility and lowering quality of life, and aging is a major risk factor for OA. However, there is a lack of insight into the specific mechanisms generating OA-associated pain in the elderly. Senescence, a cellular phenotype characterized by resistance to apoptosis and the nascent secretion of inflammatory mediators, increases with age and may contribute to OA-associated pain. Intriguingly, we have shown in mice that advanced aged and nerve injury induces senescence in DRG neurons, the first neurons in the pain circuit, and ablation of senescent cells reduces neuropathic pain. We are currently using electrophysiology in ex vivo intact DRG followed by single-cell qPCR to functionally characterize dorsal root ganglion (DRG) neurons in surgically induced models of OA. We are using retrograde tracers to target knee joint-innervating DRG and joint histology to determine the degree of OA in each limb. We are algorithmically clustering neurons by analyzing multiple aspects of intrinsic excitability (e.g. action potential properties, membrane characteristics, etc.). After functional clusters are identified, we will synergistically analyze gene expression of senescent markers (e.g. p21 and p16), cytokines (e.g. IL6), mechano- and thermotransducer channels (e.g. Trpv1, Piezo2), knee innervation, and degree of knee OA to connect specific DRG populations to knee OA-mediated pain. We have evidence that knee-innervating DRG express senescent markers in aged mice. Next, we will investigate how models of knee osteoarthritis affect the senescent DRG landscape. Funded by National Institutes of Health (R21AG075622, K99AR083486, R01DA011289, F32NS123008).