IL-33作为人工关节置换术后无菌性松动程度的诊断标志物的研究

Total joint arthroplasty is the most effective method to reconstruct joint function. However, wear particals induced-osteolysis induced leads to aseptic loosening (AL) which can affect the service life of the prosthesis. Therefore, by assessing the vivo environment around the prosthesis by means of detection and predicting the service life, early intervention is performed on patients who are about to have AL ,Significant. At present, there is no corresponding accurate detection technique in clinical practice, so it is imperative to explore biomarkers that can indicate the service life of the prosthesis. The applicant's preliminary work found that IL-33 and its related factors were abnormally expressed in the synovial fluid of patients with loose prosthesis. Because IL-33 can promote the polarization of M2 macrophages and play the role of promoting tissue repair and maintaining the balance of bone metabolism, we infer that the expression of IL-33 has a great correlation with the degree of osteolysis. This study intends to expand the sample size, analysis of IL-33 expression levels and AL severity, macrophage subtypes.confirmed its potential as an early diagnosis of AL caused by osteolytic markers and through cell experiments And animal models to elucidate the mechanism by which IL-33 exerts anti-osteolytic activity by altering macrophage subtypes. The findings will provide a new target for AL diagnosis and provide new ideas for delaying or preventing the failure of the prosthesis due to osteolysis.

人工关节置换术是重建关节功能最为有效的方式。然而当磨损颗粒诱发的骨溶解引起了假体无菌性松动AL，很快就会导致手术失败。因此通过检测手段评估假体周围的内环境，预判使用寿命，从而对即将发生AL的患者进行早期干预，意义重大。目前临床上尚无相应精准的检测技术，所以探索能提示假体使用寿命的生物标志物势在必行。申请人前期工作发现，IL-33在假体松动的患者关节液内异常表达。由于IL-33能促进M2型巨噬细胞的极化，发挥促组织修复、维持骨代谢平衡的作用，因此我们推断IL-33的表达量与骨溶解程度密切相关。本研究拟通过扩大样本量，分析IL-33表达量与AL严重程度、巨噬细胞亚型等的相关性，证实其具有作为骨溶解所致AL的早期诊断标志物的潜力，并通过细胞实验和动物模型，阐述IL-33通过改变巨噬细胞亚型发挥抗骨溶解的作用机理。研究结果将为AL的早期诊断提供新靶点和策略，为延迟或防治假体因骨溶解失效提供新思路。

人工关节置换术是重建关节功能最为有效的方式。但术后患者的人工关节可能会因磨损脱微小颗粒，这些磨损颗粒会诱发机体的免疫应异常和炎症，从而导致了假体无菌性松动，最终导致置换关节失效，需要进行二次手术进行翻修。本研究拟阐明磨损颗粒诱导产生的免疫应答调节因子IL-33是否通过影响关节腔内外巨噬细胞的极化，加重局部的炎症，从而导致骨溶解的作用机理。研究结果发现，磨损颗粒的确可以诱导局部炎性因子IL-33的高表达和关节局部炎症的发生，而磨损颗粒刺激产生的IL-33，抑制了巨噬细胞向抗炎的M2型巨噬细胞分化并促进了M1型巨噬细胞的极化。而阻断IL-33/ST2通路可以对关节局部炎症有抑制作用。我们的实验结果证实了IL-33及其受体在磨损颗粒诱导的关节相关炎症具有重要作用。在进一步的机制研究中发现磨损颗粒可以通过直接激活和极化炎性的M1型巨噬细胞来诱导炎症。综上，我们的研究表明，磨损颗粒诱导局部IL-33/ST2通路的激活，从而激活和极化M1型巨噬细胞介导的炎症，而抑制IL-33/ST2通路可以下调磨损颗粒诱导的炎症。这些结果为人工关节置换术后的患者的骨溶解、骨吸收以致无菌性松动的预防、诊断和治疗提供了新的实验依据。