Hou Chun-Han, Tang Chih-Hsin, Chen Po-Chun, Liu Ju-Fang
Department of Orthopedic Surgery, National Taiwan University Hospital, Taipei City, Taiwan.
School of Medicine, China Medical University, Taichung, Taiwan.
J Inflamm Res. 2021 Nov 13;14:5955-5967. doi: 10.2147/JIR.S314747. eCollection 2021.
BACKGROUND: It is known that osteoarthritis (OA) pathogenesis involves inflammation that drives pathologic changes and that the matricellular protein, thrombospondin-2 (TSP2), is involved in angiogenesis, carcinogenesis, and inflammation. However, how TSP2 contributes to OA inflammatory processes is unclear. OBJECTIVE: The aim of current study was to elucidate whether TSP2 could promote interleukin-6 (IL-6), a pro-inflammatory cytokine, expression in osteoarthritis synovial fibroblasts (OASFs). METHODS: The synovial fibroblasts isolated from osteoarthritis and healthy donors were incubated with recombinant TSP2 to evaluate its effect in OA pathogenesis. The SFs were incubated with recombinant TSP2, followed by determining the IL-6 expression by qPCR and Western blot. After SFs were incubated with TSP2 for different time interval, the Western blot was performed to investigate the activation of signal pathway. The different strategies including neutralizing antibodies, siRNAs, and chemical inhibitors were used to discover the signal transduction in response to TSP2 incubation in OASFs. To evaluate the therapeutic potential of TSP2 in osteoarthritis, the anterior cruciate ligament transection (ACLT) in SD rats was performed in the presence or absence of TSP neutralizing antibody treatment. RESULTS: Our investigations have revealed that TSP2 promoted IL-6 expression in OASFs in a dose-dependent manner, especially in 30 and 100 ng/mL concentration (p < 0.05). Using different strategies including neutralizing antibodies, siRNAs, and chemical inhibitors, all of which attenuated signal pathway components in OASFs, we found evidence for the involvement of integrin αβ, PI3K, Akt, and NF-κB in TSP2-mediated upregulation of IL-6 (p < 0.05). Finally, in the result of rat ACLT surgical model, we found that TSP2 neutralizing antibody had protective effects in cartilage destruction during OA progression. CONCLUSION: Thrombospondin-2 palys an important role in osteoarthritis pathogenesis and provides an opportunity to deal with osteoarthritis.
背景：已知骨关节炎（OA）的发病机制涉及驱动病理变化的炎症，并且基质细胞蛋白血小板反应蛋白-2（TSP2）参与血管生成、致癌作用和炎症。然而，TSP2如何促进OA炎症过程尚不清楚。 目的：本研究的目的是阐明TSP2是否能促进促炎细胞因子白细胞介素-6（IL-6）在骨关节炎滑膜成纤维细胞（OASFs）中的表达。 方法：将从骨关节炎患者和健康供体分离的滑膜成纤维细胞与重组TSP2孵育，以评估其在OA发病机制中的作用。将滑膜成纤维细胞与重组TSP2孵育，然后通过qPCR和蛋白质印迹法测定IL-6的表达。在滑膜成纤维细胞与TSP2孵育不同时间间隔后，进行蛋白质印迹法以研究信号通路的激活。使用包括中和抗体、小干扰RNA（siRNAs）和化学抑制剂在内的不同策略来发现OASFs中对TSP2孵育的信号转导。为了评估TSP2在骨关节炎中的治疗潜力，在有或没有TSP中和抗体治疗的情况下对SD大鼠进行前交叉韧带横断术（ACLT）。 结果：我们的研究表明，TSP2以剂量依赖的方式促进OASFs中IL-6的表达，尤其是在30和100 ng/mL浓度下（p < 0.05）。使用包括中和抗体、siRNAs和化学抑制剂在内的不同策略，所有这些策略均减弱了OASFs中的信号通路成分，我们发现整合素αβ、磷脂酰肌醇-3激酶（PI3K）、蛋白激酶B（Akt）和核因子κB（NF-κB）参与了TSP2介导的IL-6上调（p < 0.05）。最后，在大鼠ACLT手术模型的结果中，我们发现TSP2中和抗体在OA进展过程中对软骨破坏具有保护作用。 结论：血小板反应蛋白-2在骨关节炎发病机制中起重要作用，并为治疗骨关节炎提供了一个机会。
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