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首页> 外文期刊>Arthritis & Rheumatism >Chondroprotective role of the osmotically sensitive ion channel transient receptor potential vanilloid 4: Age- and sex-dependent progression of osteoarthritis in Trpv4-deficient mice
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Chondroprotective role of the osmotically sensitive ion channel transient receptor potential vanilloid 4: Age- and sex-dependent progression of osteoarthritis in Trpv4-deficient mice

机译：渗透敏感性离子通道瞬态受体电位类香草素的软骨保护作用：Trpv4缺陷小鼠骨关节炎的年龄和性别依赖性进展

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ObjectiveMechanical 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.MethodsKnee 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.ResultsDeletion 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 4-phorbol 12,13-didecanoate was eliminated in Trpv4–/– mice.ConclusionDeletion 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.
机译：目的虽然对机械信号转导的机制尚未完全了解，但是机械负荷会显着影响关节软骨的生理和病理。瞬态受体电位香草酸4（TRPV4）是Ca ++ 可渗透的离子通道，由关节软骨细胞高度表达，并可以通过渗透和机械刺激来控制。这项研究的目的是确定Trpv4在小鼠膝关节结构中的作用，并确定Trpv4 – / – 小鼠在体内是否表现出改变的Ca ++ 信号传导。方法对Trpv4 – / – 小鼠的膝关节进行组织学检查，并通过微焦点计算机断层扫描检查4、6、9和12个月大时的骨关节炎变化和骨结构。荧光成像被用来量化完整股骨软骨内对渗透压刺激的软骨细胞Ca ++ 信号传导。取决于年龄和男性性别。雄性小鼠的软骨下骨体积和钙化半月板体积也大大增加。 Trpv4 + / + 小鼠的软骨细胞对低渗应激表现出显着的Ca ++ 反应，而对高渗应激则没有。在Trpv4 – / – 小鼠中消除了对低渗胁迫或TRPV4激动剂4-phorbol 12,13-十二烷酸酯的反应。结论删除Trpv4导致缺乏渗透性诱导的Ca ++ 信号在软骨细胞中伴随着渐进的，性别依赖性的骨密度增加和骨关节炎关节变性。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。

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