The osteoarthritis associated sphingolipid sphingomyelin 34:1 causes inflammatory pain in mice

Osteoarthritis (OA) is a condition affecting synovial joints that has a multifactorial pathogenesis and where pain is the main symptom driving clinical decision making. During OA, a plethora of mediators are released by infiltrating immune cells and resident cells, such fibroblast-like synoviocytes. Although the roles of certain OA-associated disease mediators are well-understood, there are a number of molecules that are dysregulated in OA for which no role has been identified. For example, in dogs and humans with OA, dysregulation of the synovial fluid lipidome occurs and some findings have been replicated by studying the plasma lipidome in a mouse model of osteoarthritis. One upregulated lipid is the sphingomyelin N-palmitoyl-D-erythro-sphingosylphosphorylcholine (d18:1/16:0), also known as SM(d34:1), referred to here as SM. This study investigated the ability SM to cause joint pain and neuronal hyperexcitability in mice. Overnight incubation of sensory neurons with either SM or a structurally related ceramide produced a decrease in rheobase, i.e. hyperexcitability. By contrast, when injected into the knee joint of mice, SM, but not the related ceramide, evoked joint swelling, mechanical hyperalgesia and decreased digging behaviour. Moreover, when studying the excitability of retrograde traced, knee-innervating sensory neurons, only those isolated from SM-injected mice exhibited hyperexcitability. The results generated demonstrate that a dysregulated lipidome can contribute to inflammatory OA pain, further work being necessary to determine the mechanism by which SM exerts its activity.