Morgan Michael, Nazemian Vida, Ooi Li Sha, Burger Sarah, Thai Jenny, Ivanusic Jason
Department of Anatomy and Physiology, University of Melbourne, Victoria, Australia.
Osteoarthritis Cartilage. 2023 Oct;31(10):1342-1352. doi: 10.1016/j.joca.2023.06.003. Epub 2023 Jun 21.
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).
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.
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.
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 are available on request of the corresponding author.
近年来，在理解Artemin/GFRα3信号传导方面取得了重大进展，目前有越来越多的证据表明，Artemin在疼痛信号传导中发挥着重要作用，包括来自关节和骨骼的疼痛信号，以及与骨关节炎（OA）相关的疼痛信号。
本研究共使用了163只Sprague-Dawley大鼠。我们采用单碘乙酸盐（MIA）诱导的OA动物模型，结合电生理学、行为测试、蛋白质印迹分析、逆行追踪和免疫组织化学，来确定Artemin/GFRα3信号在OA疼痛发病机制中的作用。
我们发现：1）GFRα3在相当比例的膝关节传入神经元中表达；2）外源性Artemin使未接触过该物质的大鼠膝关节传入神经元敏感化；3）在MIA诱导的OA早期，Artemin在关节的关节组织中表达，但在周围骨骼中不表达；4）当病理涉及软骨下骨时，在MIA诱导的OA后期，Artemin在骨骼中的表达增加；5）在疾病后期，当膝关节组织发生炎症且软骨下骨受损时，阻断Artemin可逆转MIA诱导的膝关节和骨骼传入神经元的敏感化。
我们的研究结果表明，Artemin/GFRα3信号通过对膝关节和骨骼传入神经元的作用，在OA疼痛的发病机制中发挥作用，并表明对Artemin/GFRα3信号进行靶向操纵可能为OA疼痛的治疗带来益处。
数据可应通讯作者的要求提供。
