Activation of TRPV4 by mechanical, osmotic or pharmaceutical stimulation is anti-inflammatory blocking IL-1β mediated articular cartilage matrix destruction.
Activation of TRPV4 by mechanical, osmotic or pharmaceutical stimulation is anti-inflammatory blocking IL-1β mediated articular cartilage matrix destruction.
复制标题
DOI：
10.1016/j.joca.2020.08.002
复制
发表时间：
2021-01
影响因子：
7
通讯作者：
Knight MM
中科院分区：
文献类型：
--
作者：
Fu S;Meng H;Inamdar S;Das B;Gupta H;Wang W;Thompson CL;Knight MM
响应于一系列机械刺激，包括压缩、剪切和拉伸应变以及渗透压的相关改变，保持腕关节健康。机械传导需要对药物敏感的离子通道瞬时受体电位香草酸4（TRPV 4）。机械刺激抑制白细胞介素-1 β（IL-1β）介导的炎症信号传导，但其机制尚不清楚。本研究旨在阐明TRPV 4在这种反应中的作用。在存在或不存在IL-1β、机械（10%循环拉伸应变（CTS），0.33 Hz，24小时）或渗透负荷（200 mOsm，24小时）的情况下，在关节软骨细胞和软骨外植体中调节TRPV 4活性（GSK 205拮抗剂或GSK 1016790 A（GSK 101）激动剂）。分析一氧化氮（NO）、前列腺素E2（PGE 2）和硫酸化糖胺聚糖（sGAG）的释放和软骨生物力学。翻译后微管蛋白修饰和初级纤毛长度调节的变化进行了检查。在分离的软骨细胞中，机械负荷抑制IL-1β介导的NO和PGE 2释放。这种反应被GSK 205抑制。类似地，渗透负荷在细胞和外植体中是抗炎的，这种反应被TRPV 4抑制消除。在外植体中，GSK 101抑制IL-1β介导的NO释放，并防止软骨降解和机械性能丧失。激活后，TRPV 4纤毛定位增加，导致可溶性微管蛋白的组蛋白脱乙酰酶6（HDAC 6）依赖性调节和纤毛长度调节改变。TRPV 4的机械、渗透或药物活化调节纤毛微管蛋白的HDAC 6依赖性调节，并且是抗炎的。这项研究首次揭示了TRPV 4操纵作为抑制促炎信号传导和软骨降解的新型治疗机制的潜力。
Cartilage health is maintained in response to a range of mechanical stimuli including compressive, shear and tensile strains and associated alterations in osmolality. The osmotic-sensitive ion channel Transient Receptor Potential Vanilloid 4 (TRPV4) is required for mechanotransduction. Mechanical stimuli inhibit interleukin-1β (IL-1β) mediated inflammatory signalling, however the mechanism is unclear. This study aims to clarify the role of TRPV4 in this response. TRPV4 activity was modulated glycogen synthase kinase (GSK205 antagonist or GSK1016790 A (GSK101) agonist) in articular chondrocytes and cartilage explants in the presence or absence of IL-1β, mechanical (10% cyclic tensile strain (CTS), 0.33 Hz, 24hrs) or osmotic loading (200mOsm, 24hrs). Nitric oxide (NO), prostaglandin E2 (PGE2) and sulphated glycosaminoglycan (sGAG) release and cartilage biomechanics were analysed. Alterations in post-translational tubulin modifications and primary cilia length regulation were examined. In isolated chondrocytes, mechanical loading inhibited IL-1β mediated NO and PGE2 release. This response was inhibited by GSK205. Similarly, osmotic loading was anti-inflammatory in cells and explants, this response was abrogated by TRPV4 inhibition. In explants, GSK101 inhibited IL-1β mediated NO release and prevented cartilage degradation and loss of mechanical properties. Upon activation, TRPV4 cilia localisation was increased resulting in histone deacetylase 6 (HDAC6)-dependent modulation of soluble tubulin and altered cilia length regulation. Mechanical, osmotic or pharmaceutical activation of TRPV4 regulates HDAC6-dependent modulation of ciliary tubulin and is anti-inflammatory. This study reveals for the first time, the potential of TRPV4 manipulation as a novel therapeutic mechanism to supress pro-inflammatory signalling and cartilage degradation.
登录
查看更多内容
TRPV4和TRPA1的小分子双抑制剂，用于炎症和疼痛的衰减。
影响因子：
4.6
作者：
Kanju P;Chen Y;Lee W;Yeo M;Lee SH;Romac J;Shahid R;Fan P;Gooden DM;Simon SA;Spasojevic I;Mook RA;Liddle RA;Guilak F;Liedtke WB
通讯作者：
Liedtke WB
影响因子：
4.6
作者：
Corrigan MA;Johnson GP;Stavenschi E;Riffault M;Labour MN;Hoey DA
通讯作者：
Hoey DA
影响因子：
2.8
作者：
Kaushik, Anjan P.;Martin, James A.;Zhang, Qihong;Sheffield, Val C.;Morcuende, Jose A.
通讯作者：
Morcuende, Jose A.
影响因子：
--
作者：
Lee KL;Guevarra MD;Nguyen AM;Chua MC;Wang Y;Jacobs CR
通讯作者：
Jacobs CR
DOI：
10.1073/pnas.260501497
发表时间：
2000-12-19
影响因子：
11.1
作者：
McKinsey, TA;Zhang, CL;Olson, EN
通讯作者：
Olson, EN