Cell–cell interactions in joint pain: rheumatoid arthritis and osteoarthritis

This Pain Pictured article describes the cell–cell interactions involved in pathology and pain of rheumatoid arthritis (RA) osteoarthritis (OA), conditions which improved management is considered key by patients drives clinical decision making.22,24 According to Global Burden Disease Study 2017, RA had a global prevalence ∼20 million individuals knee hip OA ∼300 million, both being more common females than males with increasing age, peaking at 60 64 years age.37,38 Although cause joint overlap cellular inflammatory mediators, there are also differences presentation. For example, an autoimmune disease typically first affecting small joints (ie, finger/toe joints) but can progress larger joints, such as knee, whereas pathogenesis involves biomechanical processes multiple structures that ultimately lead structural deterioration most commonly afflicted. diffuse cutaneous pain, structures, including bone, synovium, ligaments, tendon synovial sheaths, infrapatellar fat pad, menisci, innervated; notably, healthy adult articular cartilage aneural. Approximately 80% innervating fibers unmyelinated (a combination afferent sympathetic fibers), remaining 20% predominantly myelinated Aδ fibers.23,28 Most nociceptors, large population “silent” nociceptors only become active after sensitization.40 Joint characterized inflammation, degradation, bone erosion, marrow lesions. Synoviocytes proliferate, developing proinflammatory catabolic phenotype, while numerous immune cells (macrophages, T cells, B plasma mast dendritic neutrophils) infiltrate synovium fluid (SF) where they produce factors, chemoattractants recruit additional cells.10,18 The combined infiltration drive autoimmunity local autoantibody production feature unique when compared OA. In joint, changes include alternations chondrocyte density, activity—cartilage erosion followed hypertrophy generation matrix degradation products alongside mediator secretion; macrophages, CD4+ lymphocytes; synoviocytes proliferate (albeit lesser extent RA) release mediators; subchondral turnover because increased osteoblast osteoclast activity result sclerotic osteophyte formation, lesions altered vascular neuronal innervation.5,24,34,45 Cell–cell occur primarily through soluble power demonstrated acellularized human OA–SF sensitizing mouse knee-innervating sensory neurons, thus highlighting importance mediators driving arthritis.11 With regard specific arthritic some between those OA, eg, nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin provide relief from inflammation conditions. It should be noted however even medically controlled.4 factors locally produced could potentially act nociceptor-expressed receptors tumor necrosis factor α (TNFα),25 interleukin 1β (IL-1β),30 IL-6,15 IL-17.14 targeting TNFα, IL-1β, IL-6 efficacious treating RA, this has not yet been replicated for all implicated pathogenesis. By contrast, nerve growth factor, causes hyperalgesia,29 reportedly elevated SF,3 trials highlight anti-nerve antibodies promising therapeutic pain7,41 have investigated RA-focused trials. Specifically toll-like receptor 2 (TLR2), activated 32-amino-acid aggrecan fragment found SF, highlighted potential analgesic target.19,32 addition, express voltage-gated sodium channel 1.8 (NaV1.8) innervate osteochondral channels play role preclinical models,45 makes nociceptor subset target considering associated humans.5 Multiple studies indicate SF pH decreased so OA,13,17,20,21 accordingly, ion extracellular protons, acid-sensing 3 (ASIC3)26,42 transient vanilloid 1 (TRPV1),9 linked mechanical hypersensitivity experimental models. unclear if protons one cell type responsible these effects. lipid lysophosphatidylcholine, directly activate ASIC3.31 Finally, autoantibodies stimulate forming complexes proteins collagen II then activating neuronally expressed Fcγ I8,35; other CXCL1/2.44 addition peripheral mechanisms, central processing,16,27 substantial debate field clinically important, events likely simpler fewer side processing, models, expression TLR4 spinal microglia its endogenous ligands, HMGB1, pain-like behavior sex-specific cell-specific manner.1,2 Moreover, contributes HMGB1-mediated females, on participates sexes.36 Similarly, proliferation activation correlates pain.39,43 However, neuroimmune restricted proximal distal endings primary macrophage into dorsal root ganglia illustrated pain.6,33 summary, involve multitude plethora mechanisms involved. Increasing mechanistic understanding occurring will hopefully identification new strategies, use gene therapy modulate neurons.12 Conflict interest statement authors no conflicts declare.