Orita Sumihisa, Suzuki Miyako, Inage Kazuhide, Shiga Yasuhiro, Fujimoto Kazuki, Kanamoto Hirohito, Abe Koki, Inoue Masahiro, Kinoshita Hideyuki, Norimoto Masaki, Umimura Tomotaka, Yamauchi Kazuyo, Aoki Yasuchika, Nakamura Junichi, Matsuura Yusuke, Hagiwara Shigeo, Eguchi Yawara, Akazawa Tsutomu, Takahashi Kazuhisa, Furuya Takeo, Koda Masao, Ohtori Seiji
Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
Department of Orthopaedic Surgery, Eastern Chiba Medical Center, Chiba, Japan.
Spine Surg Relat Res. 2018 Apr 7;2(3):230-235. doi: 10.22603/ssrr.2017-0086. eCollection 2018.
Osteoporosis can produce a persistent state of pain known as osteoporotic pain. One proposed mechanism of this pathology is increased calcitonin gene-related peptide (CGRP; a marker related to inflammatory pain) expression in the dorsal root ganglia (DRG) innervating osteoporotic vertebrae. Alternatively, a previous study revealed that axial loading caused osteoporotic pain in a rodent model of coccygeal vertebrae compression. Because this compression model is associated with trauma, additional mechanistic studies of osteoporotic pain in the absence of trauma are required. The current study aimedto evaluate the expression and relative distribution of transient receptor potential vanilloid 4 (TRPV4), a pain-related mechanoreceptor, in ovariectomized (OVX) osteoporotic rats.
CGRP-immunoreactive (-ir) and TRPV4-ir DRG neurons innervating the L3 vertebrae of Sprague-Dawley rats were labeled with a neurotracer, FluoroGold. Intravertebral pH was also measured during the neurotracer procedure. TRPV4-ir/CGRP-ir FluoroGold-positive DRG neurons were quantified in sham control and OVX rats ( = 10, ea). The threshold for statistical significance was set at < 0.05.
There was no statistical difference in the number of FluoroGold-positive DRG neurons between groups; however, there were significantly more CGRP-ir/TRPV4-ir FluoroGold-positive DRG neurons in the OVX group compared with the sham control group ( < 0.05) as well as the significantly increased molecular production of each peptide. Intravertebral pH was also lower in the OVX group compared with the sham control group ( < 0.05).
Sensory neurons innervating osteoporotic vertebrae exhibited increased expression of co-localized CGRP and TRPV4 in OVX osteoporotic rats. Additionally, intravertebral pH was low in the vicinity osteoporotic vertebrae. Considering that TRPV4 is a mechanosensitive nociceptor that is activated in acidic environments, its upregulation may be associated with the pathology of osteoporotic pain derived from microinflammation involved in osteoporosis.
骨质疏松症可产生一种持续的疼痛状态，即骨质疏松性疼痛。这种病理状态的一种推测机制是，支配骨质疏松椎骨的背根神经节（DRG）中降钙素基因相关肽（CGRP；一种与炎性疼痛相关的标志物）表达增加。另外，先前的一项研究表明，在尾椎压缩的啮齿动物模型中，轴向负荷可导致骨质疏松性疼痛。由于这种压缩模型与创伤有关，因此需要在无创伤的情况下对骨质疏松性疼痛进行更多的机制研究。本研究旨在评估瞬时受体电位香草酸亚型4（TRPV4，一种与疼痛相关的机械感受器）在去卵巢（OVX）骨质疏松大鼠中的表达及相对分布。
用神经示踪剂荧光金标记支配Sprague-Dawley大鼠L3椎骨的CGRP免疫反应性（-ir）和TRPV4-ir DRG神经元。在神经示踪过程中还测量了椎体内pH值。对假手术对照组和OVX大鼠（每组n = 10）中TRPV4-ir/CGRP-ir荧光金阳性DRG神经元进行定量分析。统计学显著性阈值设定为P < 0.05。
两组间荧光金阳性DRG神经元数量无统计学差异；然而，与假手术对照组相比，OVX组中CGRP-ir/TRPV4-ir荧光金阳性DRG神经元明显更多（P < 0.05），且每种肽的分子产量也显著增加。与假手术对照组相比，OVX组的椎体内pH值也更低（P < 0.05）。
在OVX骨质疏松大鼠中，支配骨质疏松椎骨的感觉神经元中CGRP和TRPV4的共定位表达增加。此外，骨质疏松椎骨附近的椎体内pH值较低。鉴于TRPV4是一种在酸性环境中被激活的机械敏感伤害感受器，其上调可能与骨质疏松症相关的微炎症引起的骨质疏松性疼痛的病理过程有关。
