Rationale: Pigmented villonodular synovitis (PVNS) is a destructive benign tumor-like hyperplastic disease that occurs in synovial tissue. Fibroblast-like synoviocytes (FLS) are the predominant cell type comprising the structure of the PVNS synovial lining layer. Due to a high recurrence rate, high invasion, migration, and cartilage destruction ability, PVNS causes substantial damage to patients and the efficacy of surgical resection is not satisfactory. Therefore, exploring the pathogenesis and identifying novel therapeutic targets for PVNS are urgently required. Currently, the pathogenesis of PVNS remains unclear, and there is uncertainty and controversy regarding whether PVNS is an inflammatory or a neoplastic disease. Cadherin-11 is a classical molecule that mediates hemophilic cell-to-cell adhesion in FLS and plays an important role in the normal synovium lining layer formation. This study aimed to explore the role of inflammation and cadherin-11 in PVNS pathogenesis and determine the effects of cadherin-11 as a molecular target for PVNS treatment./nMethods: FLS were primarily cultured from PVNS patients during arthroscopic synovectomy. The level of cytokines in the PVNS synovial fluid was evaluated using a human antibody array. Cadherin-11 expression of PVNS FLS was detected by qPCR, Western blots, tissue immunohistochemistry, and cell immunofluorescence. Cadherin-11 was down-regulated by siRNA or up-regulated with a plasmid, with or without inflammatory factor stimulation, and PI3K/Akt was inhibited with LY294002. The capacity of migration and invasion of PVNS FLS was tested using Transwell and wound-healing assays. Activation of the nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways was detected by Western blots. Chondrocyte damage by PVNS FLS was assessed with a co-culture assay./nResults: Inflammatory factors (IL-1β and TNF-α) in the synovial fluid of PVNS patients were significantly up-regulated. Cadherin-11 was highly expressed in the FLS of PVNS patients, and positively correlated with recurrence, extra-articular migration, and cartilage destruction of PVNS. Knocking down of cadherin-11 inhibited the migration and invasion of PVNS FLS. Moreover, inflammatory factors up-regulated the expression of cadherin-11, which activated the NF-κB and MAPK signaling pathways and led to cartilage destruction. Inhibition of cadherin-11 blocked IL-1β- and TNF-α-induced activation of the above pathways, migration and invasion of PVNS FLS, and damage of chondrocyte. In addition, the elevation of cadherin-11 expression, together with the migration and invasion, of PVNS FLS was down-regulated by the inhibition of the PI3K/Akt signaling pathway./nConclusions: Cadherin-11 plays an important role in the pathogenesis of PVNS and forms a positive feedback loop with inflammatory factors, which further activates the NF-κB and MAPK pathways to trigger an inflammatory cascade. Cadherin-11-mediated inflammation results in PVNS with high recurrence, invasiveness, and strong cartilage destruction ability, and eventually promotes the transformation of PVNS from the initial inflammatory disease to neoplastic disease. Thus, inhibition of cadherin-11 together with its related inflammatory reaction, represents a new therapeutic strategy for PVNS.

中文翻译：

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Cadherin-11与炎性因子协同作用，促进色素性绒毛状滑膜炎中成纤维样滑膜细胞的迁移和侵袭。

理由：色素沉着绒毛状滑膜炎（PVNS）是一种发生在滑膜组织中的破坏性良性肿瘤样增生性疾病。成纤维样滑膜细胞（FLS）是主要的细胞类型，包括PVNS滑膜衬里层的结构。由于高复发率，高侵袭，迁移和软骨破坏能力，PVNS对患者造成实质性损害，并且手术切除的效果不令人满意。因此，迫切需要探索PVNS的发病机理并确定新的治疗靶标。目前，PVNS的发病机理仍不清楚，关于PVNS是炎性疾病还是赘生性疾病存在不确定性和争议。Cadherin-11是经典分子，可介导FLS中血友病细胞间的粘附，并在正常滑膜衬里层形成中起重要作用。这项研究旨在探讨炎症和钙黏着蛋白11在PVNS发病机制中的作用，并确定钙黏着蛋白11作为PVNS治疗的分子靶标的作用。方法： FLS主要在关节镜滑膜切除术中从PVNS患者中培养。使用人抗体阵列评估PVNS滑液中的细胞因子水平。通过qPCR，Western印迹，组织免疫组织化学和细胞免疫荧光检测PVNS FLS的Cadherin-11表达。在有或没有炎症因子刺激的情况下，Cadherin-11被siRNA下调或被质粒上调，而LY294002抑制PI3K / Akt。PVNS FLS的迁移和侵袭能力使用Transwell和伤口愈合试验进行了测试。Western印迹检测核因子-κB（NF-κB）和丝裂原激活的蛋白激酶（MAPK）通路的激活。通过共培养测定法评估PVNS FLS对软骨细胞的损害。/n结果：PVNS患者滑液中的炎症因子（IL-1β和TNF-α）显着上调。Cadherin-11在PVNS患者的FLS中高表达，并与PVNS的复发，关节外迁移和软骨破坏呈正相关。敲低钙黏着蛋白11抑制了PVNS FLS的迁移和侵袭。此外，炎性因子上调了钙黏着蛋白11的表达，从而激活了NF-κB和MAPK信号通路并导致软骨破坏。抑制钙粘着蛋白11阻断了IL-1β和TNF-α诱导的上述途径的激活，PVNS FLS的迁移和侵袭以及软骨细胞的损伤。此外，通过抑制PI3K / Akt信号通路，下调了PVNS FLS cadherin-11表达的升高以及迁移和侵袭。结论： Cadherin-11在PVNS的发病机制中起重要作用，并与炎性因子形成正反馈回路，进一步激活NF-κB和MAPK途径，引发炎性级联反应。Cadherin-11-介导的炎症导致PVNS具有高复发性，侵袭性和强大的软骨破坏能力，并最终促进PVNS从最初的炎性疾病向肿瘤性疾病的转化。因此，抑制钙粘着蛋白11及其相关的炎症反应代表了PVNS的新治疗策略。