雌激素通过cadherin-11加重颞下颌关节炎症机制的研究

Women of childbearing age are more likely than men to experience temporomandibular disorders, with pain as the main symptom. Whether sex hormones are involved in the sexual dimorphism of Temporomandibular joint (TMJ) inflammation and pain remains to be elucidated. Recently, cadherin-11 was reported to play an essential role in the formation of synovium, and also perform a critical role in synovial inflammation and arthritis pathology. Cadherin-/- deficient mice showed significantly less inflammation measured by joint swelling and clinical score. Moreover, treatment of cadherin-11 antibody displayed significantly delayed onset of disease and reduced severity of arthritis in mouse model. However, the expression of cadherin-11 in TMJ synovium and how cadherin-11 involved in the process of TMJ inflammation and the modulation of cadherin-11 are largely unknown. It has been well reported that estrogen have the ability to regulate cadherin-11 expression in isolated endometrial stromal cells. Moreover, estrogen receptor specific antagonist, ICI 182,780, was capable of reducing stromal cadherin-11 expression. These indicate that E2 may have the ability to modulate the expression of cadherin-11 in TMJ synovium. Thus, we hypothesized that estrogen may involve in TMD pain through modulating the expression of cadherin-11 in the process of joint inflammation. We, therefore, explored whether cadherin-11 expression could be modulated by estrogen, and if so, whether the effects of estrogen in the inflamed TMJ can be blocked by cadherin-11.

颞下颌关节紊乱病（temporomandibular joint diseases， TMD）多发于育龄期女性，疼痛为其重要临床表现；而滑膜炎症是TMD相关疼痛的主要原因之一。雌激素是否参与TMD疼痛及参与TMD疼痛的机制，目前尚不完全明了。钙粘附分子-11（cadherin-11）在关节炎症中发挥了至关重要的作用。雌激素能否通过cadherin-11促进颞下颌关节滑膜炎，目前尚未可知。本课题将在实验性颞下颌关节炎症动物模型及原代培养的滑膜细胞中，观察雌激素能否上调cadherin-11的表达；观察阻断cadherin-11能否减轻颞下颌关节炎症及雌激素对关节炎症的加重作用；探讨雌激素调控cadherin-11的机制，以及cadherin-11参与关节炎症的机制。这将为探索TMD的新的治疗靶点提供理论和实验依据，并为理解TMD及其他性别差异疾病提供新的思路，具有非常重要的临床和科学意义。

颞下颌关节紊乱病（temporomandibular joint diseases， TMD）多发于育龄期女性，疼痛为其重要临床表现；而滑膜炎症是TMD相关疼痛的主要原因之一。雌激素是否参与TMD疼痛及其参与TMD疼痛的机制，目前尚不完全明了。钙粘附分子-11（cadherin-11）在关节炎症中发挥了至关重要的作用。本课题旨在探讨雌激素能否通过cadherin-11调控颞下颌关节（TMJ）滑膜炎症。本项目研究发现，雌激素以剂量依赖的方式上调炎性颞下颌关节（TMJ）增生滑膜组织及原代培养的滑膜细胞中Cadherin-11的表达； 雌激素可以进一步促进TNF-α诱导的滑膜细胞中cadherins-11的上调；阻断cadherin-11可以减轻大鼠TMJ机械性痛觉增敏以及增生滑膜细胞中iNOS的表达；阻断cadherin-11能抑制TNF-α诱导 滑膜细胞中促炎细胞因子的转录。此外本研究还发现，雌激素能够加重炎症滑膜组织中M1型巨噬细胞的浸润；雌激素可上调M1型巨噬细胞相关促炎基因如iNOS的表达，并抑制M2型巨噬细胞相关基因如IL-10、arginased的表达;雌激素主要促进cadherin-11在M1型而非M2型巨噬细胞中的表达；重要的是，阻断cadherin-11能够部分逆转雌激素诱导的M1型巨噬细胞的激活和TMJ炎症的加重；且阻断雌激素受体能够抑制M1型巨噬细胞的激活以及cadherin-11的表达。综上所述，本项目发现雌激素能够通过cadherin-11促进巨噬细胞浸润，加重TMJ滑膜炎症，进而加重TMD相关疼痛；阻断雌激素受体以及cadherin-11能够减轻TMJ滑膜炎症及相关疼痛。这将为探索TMD的新的治疗靶点提供理论和实验依据，并为理解TMD及其他性别差异疾病提供新的思路，具有非常重要的临床和科学意义。