Clark Andrea L, Votta Bartholomew J, Kumar Sanjay, Liedtke Wolfgang, Guilak Farshid
Duke University Medical Center, Durham, North Carolina.
Arthritis Rheum. 2010 Oct;62(10):2973-83. doi: 10.1002/art.27624.
Mechanical loading significantly influences the physiology and pathology of articular cartilage, although the mechanisms of mechanical signal transduction are not fully understood. Transient receptor potential vanilloid 4 (TRPV4) is a Ca(++)-permeable ion channel that is highly expressed by articular chondrocytes and can be gated by osmotic and mechanical stimuli. The goal of this study was to determine the role of Trpv4 in the structure of the mouse knee joint and to determine whether Trpv4(-/-) mice exhibit altered Ca(++) signaling in response to osmotic challenge.
Knee joints of Trpv4(-/-) mice were examined histologically and by microfocal computed tomography for osteoarthritic changes and bone structure at ages 4, 6, 9, and 12 months. Fluorescence imaging was used to quantify chondrocytic Ca(++) signaling within intact femoral cartilage in response to osmotic stimuli.
Deletion of Trpv4 resulted in severe osteoarthritic changes, including cartilage fibrillation, eburnation, and loss of proteoglycans, that were dependent on age and male sex. Subchondral bone volume and calcified meniscal volume were greatly increased, again in male mice. Chondrocytes from Trpv4(+/+) mice demonstrated significant Ca(++) responses to hypo-osmotic stress but not to hyperosmotic stress. The response to hypo-osmotic stress or to the TRPV4 agonist 4α-phorbol 12,13-didecanoate was eliminated in Trpv4(-/-) mice.
Deletion of Trpv4 leads to a lack of osmotically induced Ca(++) signaling in articular chondrocytes, accompanied by progressive, sex-dependent increases in bone density and osteoarthritic joint degeneration. These findings suggest a critical role for TRPV4-mediated Ca(++) signaling in the maintenance of joint health and normal skeletal structure.
机械负荷对关节软骨的生理和病理有显著影响，尽管机械信号转导机制尚未完全明确。瞬时受体电位香草酸亚型4（TRPV4）是一种对Ca(++)通透的离子通道，在关节软骨细胞中高表达，可被渗透压和机械刺激激活。本研究旨在确定Trpv4在小鼠膝关节结构中的作用，并确定Trpv4基因敲除（Trpv4(-/-)）小鼠在受到渗透压挑战时是否表现出Ca(++)信号改变。
对4、6、9和12月龄的Trpv4(-/-)小鼠膝关节进行组织学检查，并通过微焦点计算机断层扫描观察骨关节炎变化和骨结构。利用荧光成像技术量化完整股骨软骨内软骨细胞对渗透压刺激的Ca(++)信号。
Trpv4基因缺失导致严重的骨关节炎变化，包括软骨纤维化、骨质象牙化和蛋白聚糖丢失，这些变化与年龄和雄性性别有关。在雄性小鼠中，软骨下骨体积和钙化半月板体积也大幅增加。来自野生型（Trpv4(+/+)）小鼠的软骨细胞对低渗应激表现出显著的Ca(++)反应，但对高渗应激无反应。Trpv4(-/-)小鼠对低渗应激或TRPV4激动剂4α-佛波醇12,13-十四酸酯的反应消失。
Trpv4基因缺失导致关节软骨细胞中缺乏渗透压诱导的Ca(++)信号，同时伴有骨密度和骨关节炎性关节退变的渐进性、性别依赖性增加。这些发现表明TRPV4介导的Ca(++)信号在维持关节健康和正常骨骼结构中起关键作用。
