Background The pathophysiology of osteoarthritis (OA) involves wear and tear, and a state of low-grade inflammation. Tissue repair responses include transforming growth factor beta (TGFβ)-induced myofibroblast production of extracellular matrix. Fibronectins are an essential part of the extracellular matrix, and injection of fibronectin fragments into rabbit joints is a previously established animal model of OA. Fibronectin containing the ED-A domain is currently being used as drug delivery target in the development of anti-inflammatory drugs (e.g. Dekavil). Methods In this study, samples of synovial membrane were obtained from patients with knee OA undergoing joint replacement surgery. Immunostaining for ED-A fibronectin and the myofibroblast marker alpha smooth muscle actin (αSMA) was performed on fibroblast-like synovial cells (FLS) and synovial membranes. RAW 264.7 macrophages were incubated with recombinant ED-A fibronectin. Results The staining of ED-A fibronectin in OA FLS was increased by TGFβ but not by TNFα, lipopolysaccharide, or IL-6 (n = 3). ED-A fibronectin co-stained with the myofibroblast marker αSMA in both the OA FLS (n = 3) and in the OA synovial membranes (n = 8). ED-A fibronectin staining was associated with both number of lining layer cells (rho = 0.85 and p = 0.011) and sublining cells (rho = 0.88 and p = 0.007) in the OA synovium (n = 8), and co-distributed with TNFα (n = 5). Recombinant ED-A fibronectin increased the production of TNFα by RAW 264.7 macrophages (n = 3). Conclusions The disease process in OA shares features with the chronic wound healing response. Our findings support utilizing ED-A fibronectin for drug delivery or therapeutic targeting to reduce pro-inflammatory responses in OA.

中文翻译：

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额外结构域 A 纤连蛋白的成纤维细胞样滑膜细胞产生与骨关节炎中的炎症有关。

背景骨关节炎 (OA) 的病理生理学涉及磨损和低度炎症状态。组织修复反应包括转化生长因子β (TGFβ) 诱导的细胞外基质的肌成纤维细胞产生。纤连蛋白是细胞外基质的重要组成部分，将纤连蛋白片段注射到兔关节是先前建立的 OA 动物模型。含有 ED-A 结构域的纤连蛋白目前被用作开发抗炎药（例如 Dekavil）的药物递送靶标。方法 在本研究中，从接受关节置换手术的膝关节 OA 患者中获取滑膜样本。在成纤维细胞样滑膜细胞 (FLS) 和滑膜上进行 ED-A 纤连蛋白和肌成纤维细胞标志物 α 平滑肌肌动蛋白 (αSMA) 的免疫染色。RAW 264.7 巨噬细胞与重组 ED-A 纤连蛋白一起孵育。结果 TGFβ 增加了 OA FLS 中 ED-A 纤连蛋白的染色，但 TNFα、脂多糖或 IL-6 没有增加（n = 3）。在 OA FLS (n = 3) 和 OA 滑膜 (n = 8) 中，ED-A 纤连蛋白与肌成纤维细胞标记物 αSMA 共染色。ED-A 纤连蛋白染色与 OA 滑膜 (n = 8) 中衬层细胞 (rho = 0.85 和 p = 0.011) 和亚衬层细胞 (rho = 0.88 和 p = 0.007) 的数量相关，并与TNFα（n = 5）。重组 ED-A 纤连蛋白增加了 RAW 264.7 巨噬细胞 (n = 3) 产生的 TNFα。结论 OA 的疾病过程与慢性伤口愈合反应具有共同特征。我们的研究结果支持利用 ED-A 纤连蛋白进行药物递送或治疗靶向，以减少 OA 中的促炎反应。