Transient receptor potential vanilloid 4 (TRPV4) is a multi-modally activated cation channel that mediates mechanotransduction pathways by which musculoskeletal tissues respond to mechanical load and regulate tissue health. Using conditional knockout mice, we investigated the role of in regulating intervertebral disc (IVD) health and injury-induced IVD degeneration. ( KO) mice were used to knockout in all type 2 collagen-expressing cells. Effects of gene targeting alone was assessed in lumbar spines, using vertebral bone length measurement, histological, immunohistochemistry and gene expression analyses, and mechanical testing. Disc puncture was performed on caudal IVDs of wild-type (WT) and KO mice at 2.5- and 6.5-months-of-age. Six weeks after puncture (4- and 8-months-of-age at sacrifice), caudal spines were assessed using histological analyses. While loss of did not significantly alter vertebral bone length and tissue histomorphology compared to age-matched WT mice, KO mice showed decreased proteoglycan and PRG4 staining in the annulus fibrosus compared to WT. At the gene level, KO mice showed significantly increased expression of , , and compared to WT. Functionally, loss of was associated with significantly increased neutral zone length in lumbar IVDs. Following puncture, both KO and WT mice showed similar signs of degeneration at the site of injury. Interestingly, loss of prevented mechanically-induced degeneration in IVDs adjacent to sites of injury. These studies suggest a role for in regulating extracellular matrix synthesis and mediating the response of IVD tissues to mechanical stress.

中文翻译：

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瞬时受体电位香草酸 4 调节细胞外基质组成并介导小鼠模型中负荷诱导的椎间盘退变


瞬时受体电位香草酸 4 (TRPV4) 是一种多模式激活的阳离子通道，可介导肌肉骨骼组织对机械负荷做出反应并调节组织健康的机械转导途径。使用条件敲除小鼠，我们研究了在调节椎间盘（IVD）健康和损伤引起的 IVD 退化中的作用。 (KO) 小鼠用于敲除所有 2 型胶原蛋白表达细胞。使用椎骨长度测量、组织学、免疫组织化学和基因表达分析以及机械测试来评估单独基因靶向对腰椎的影响。对 2.5 个月和 6.5 个月龄的野生型 (WT) 和 KO 小鼠的尾部 IVD 进行椎间盘穿刺。穿刺后六周（处死时 4 个月和 8 个月大），使用组织学分析评估尾棘。虽然与年龄匹配的WT小鼠相比，KO小鼠的椎骨长度和组织组织形态学没有显着改变，但与WT相比，KO小鼠的纤维环中的蛋白聚糖和PRG4染色减少。在基因水平上，与 WT 相比，KO 小鼠表现出 、 、 和 的表达显着增加。从功能上来说，腰椎 IVD 中中性区长度的显着增加与 丢失相关。穿刺后，KO 和 WT 小鼠在损伤部位表现出相似的退化迹象。有趣的是，损伤部位附近 IVD 的损失可以防止机械引起的退化。这些研究表明其在调节细胞外基质合成和介导 IVD 组织对机械应力的反应中发挥作用。