雌激素（E2）水平下降导致软骨基质代谢失衡可引发绝经后骨性关节炎（OA），但其机制尚不明确。我们前期研究发现：伴随绝经后OA患者关节液渗透压下降，软骨细胞的容积敏感性LRRC8A氯通道分布紊乱，氯电流下降；E2抑制低渗诱导的正常软骨细胞LRRC8A氯电流；E2刺激或者干扰LRRC8A均可升高Ⅱ型胶原的表达，下调软骨基质金属蛋白酶-13的表达；提示持续低渗条件可能导致LRRC8A氯通道过度激活而功能下降，从而介导E2下降引发的软骨基质合成-分解代谢失衡。因此，本研究拟采用膜片钳、CoIP、ChIP、LRRC8A-/-动物模型等技术，从体内外两个层次探讨绝经后OA 软骨中LRRC8A氯通道功能下降在E2异常引发软骨基质代谢失衡中的作用及分子机制。进一步解析E2水平下降导致软骨基质代谢失衡的发病机理，将为阐明绝经后OA的发病机制提供新的视角，为治疗绝经后OA提供新的靶点。

The imbalance of cartilage metabolism is ascribed to the estrogen (E2) decrease, which could lead to post-menopausal osteoarthritis (OA). However, the mechanism of this process is still unclear. Previously we have found that osmotic pressure decreasing of the synovial fluid associates the disturbance of volume sensitivity of LRRC8A chloride channel distribution and the chondrocytes chloride current decreasing in the postmenopausal patients with OA. As E2 inhibits hypotonic solution, it induces LRRC8A chloride current in the normal chondrocytes. Moreover, E2 or LRRC8A suppression could increases collagen type II expression, and reduces the expression of matrix metalloproteinases-13. These results suggest that LRRC8A chloride channel is supposed to be over-activated, since its function may be declined under a hypotonic condition. LRRC8A chloride channel dysfunction is supposed to play a pivotal role in the cartilage matrix imbalance, which being induced by E2 decreasing. Therefore, this study intends to use patch clamp, CoIP, ChIP, LRRC8A-/- animal model and other technologies to explore the role and molecular mechanism of the decreased function of LRRC8A chloride channel in E2-induced cartilage matrix metabolism imbalance in postmenopausal OA. Further analysis of cartilage matrix metabolism imbalance pathogenesis under E2 decreasing will be performed. Thus, the findings of this project will provide a new perspective to clarify postmenopausal OA pathogenesis and a new target for postmenopausal OA treatment.