Department of Anatomy and Physiology, University of Melbourne, Victoria, Australia.
Department of Biochemistry and Pharmacology, University of Melbourne, Victoria, Australia.
Bone. 2024 Dec;189:117260. doi: 10.1016/j.bone.2024.117260. Epub 2024 Sep 17.
There is emerging evidence that Brain Derived Neurotrophic Factor (BDNF), and one of its receptors TrkB, play important roles in the pathogenesis of osteoarthritis (OA) pain. Whilst these studies clearly highlight the potential for targeting BDNF/TrkB signaling to treat OA pain, the mechanism for how BDNF/TrkB signaling contributes to OA pain remains unclear. 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 BDNF/TrkB signaling in the pathogenesis of OA pain. We found that: 1) TrkB is expressed in myelinated medium diameter neurons that innervate the knee joint and bone in naïve animals; 2) peripheral application of BDNF increases the sensitivity of Aδ, but not C knee joint and bone afferent neurons, in response to mechanical stimulation, in naïve animals; 3) BDNF expression increases in synovial tissue in early MIA-induced OA, when pathology is confined to the joint, and in the subchondral bone in late MIA-induced OA, when there is additional damage to the surrounding bone; and 4) TrkB inhibition reverses MIA-induced changes in the sensitivity of Aδ but not C knee joint afferent neurons early in MIA-induced OA, and Aδ but not C bone afferent neurons late in MIA-induced OA. Our findings suggest that BDNF/TrkB signaling may have a role to play in the pathogenesis of OA pain, through effects on knee joint afferent neurons early in disease when there is inflammation confined to the joint, and bone afferent neurons late in disease when there is involvement of damage to subchondral bone. Targeted manipulation of BDNF/TrkB signaling may provide therapeutic benefit for the management of OA pain.
有新的证据表明脑源性神经营养因子（BDNF）及其受体 TrkB 在骨关节炎（OA）疼痛的发病机制中发挥重要作用。虽然这些研究清楚地强调了靶向 BDNF/TrkB 信号转导治疗 OA 疼痛的潜力，但 BDNF/TrkB 信号转导如何导致 OA 疼痛的机制尚不清楚。在这项研究中，我们使用了单碘乙酸（MIA）诱导的 OA 动物模型，结合电生理学、行为测试、Western blot 分析、逆行追踪和免疫组织化学，以确定 BDNF/TrkB 信号在 OA 疼痛发病机制中的作用。我们发现：1）TrkB 表达在支配膝关节和骨骼的有髓鞘中直径神经元中在天真的动物; 2）BDNF 的外周应用增加了 Aδ的敏感性，但不是 C 膝关节和骨骼传入神经元，在机械刺激下，在天真的动物; 3）BDNF 表达在滑膜组织中增加在早期 MIA 诱导的 OA 中，当病理学仅限于关节，并且在晚期 MIA 诱导的 OA 中在软骨下骨中，当周围骨骼有额外的损伤时; 和 4）TrkB 抑制逆转了 MIA 诱导的 Aδ但不是 C 膝关节传入神经元的敏感性早期在 MIA 诱导的 OA 中，以及 Aδ但不是 C 骨传入神经元晚期在 MIA 诱导的 OA 中。我们的研究结果表明，BDNF/TrkB 信号可能通过在疾病早期局限于关节的炎症时对膝关节传入神经元的影响，以及在涉及软骨下骨损伤的疾病晚期对骨骼传入神经元的影响，在 OA 疼痛的发病机制中发挥作用。BDNF/TrkB 信号的靶向操纵可能为 OA 疼痛的管理提供治疗益处。
