Artemin Sensitizes Nociceptors That Innervate the Osteoarthritic Joint to Produce Pain

OBJECTIVE:There have been significant developments in understanding artemin/GFRα3 signaling in recent years, and there is now accumulating evidence that artemin has important roles to play in pain signaling, including that derived from joint and bone, and that associated with osteorthritis (OA).METHODS:A total of 163 Sprague-Dawley rats were used in this study. We used an animal model of mono-iodoacetate (MIA)-induced OA, in combination with electrophysiology, behavioral testing, Western blot analysis, and retrograde tracing and immunohistochemistry, to identify roles for artemin/GFRα3 signaling in the pathogenesis of OA pain.RESULTS:We have found that: 1) GFRα3 is expressed in a substantial proportion of knee joint afferent neurons; 2) exogenous artemin sensitizes knee joint afferent neurons in naïve rats; 3) artemin is expressed in articular tissues of the joint, but not surrounding bone, early in MIA-induced OA; 4) artemin expression increases in bone later in MIA-induced OA when pathology involves subchondral bone; and 5) sequestration of artemin reverses MIA-induced sensitization of both knee joint and bone afferent neurons late in disease when there is inflammation of knee joint tissues and damage to the subchondral bone.CONCLUSIONS:Our findings show that artemin/GFRα3 signaling has a role to play in the pathogenesis of OA pain, through effects on both knee joint and bone afferent neurons, and suggest that targeted manipulation of artemin/GFRα3 signaling may provide therapeutic benefit for the management of OA pain.DATA AVAILABILITY:Data are available on request of the corresponding author.