Shelef Miriam A, Bennin David A, Yasmin Nihad, Warner Thomas F, Ludwig Thomas, Beggs Hilary E, Huttenlocher Anna
Arthritis Res Ther. 2014 Oct 4;16(5):464. doi: 10.1186/s13075-014-0464-6.
Synovial fibroblasts invade cartilage and bone, leading to joint destruction in rheumatoid arthritis. However, the mechanisms that regulate synovial fibroblast invasion are not well understood. Focal adhesion kinase (FAK) has been implicated in cellular invasion in several cell types, and FAK inhibitors are in clinical trials for cancer treatment. Little is known about the role of FAK in inflammatory arthritis, but, given its expression in synovial tissue, its known role in invasion in other cells and the potential clinical availability of FAK inhibitors, it is important to determine if FAK contributes to synovial fibroblast invasion and inflammatory arthritis.
After treatment with FAK inhibitors, invasiveness of human rheumatoid synovial fibroblasts was determined with Matrigel invasion chambers. Migration and focal matrix degradation, two components of cellular invasion, were assessed in FAK-inhibited rheumatoid synovial fibroblasts by transwell assay and microscopic examination of fluorescent gelatin degradation, respectively. Using mice with tumor necrosis factor α (TNFα)-induced arthritis in which fak could be inducibly deleted, invasion and migration by FAK-deficient murine arthritic synovial fibroblasts were determined as described above and arthritis was clinically and pathologically scored in FAK-deficient mice.
Inhibition of FAK in human rheumatoid synovial fibroblasts impaired cellular invasion and migration. Focal matrix degradation occurred both centrally and at focal adhesions, the latter being a novel site for matrix degradation in synovial fibroblasts, but degradation was unaltered with FAK inhibitors. Loss of FAK reduced invasion in murine arthritic synovial fibroblasts, but not migration or TNFα-induced arthritis severity and joint erosions.
FAK inhibitors reduce synovial fibroblast invasion and migration, but synovial fibroblast migration and TNFα-induced arthritis do not rely on FAK itself. Thus, inhibition of FAK alone is unlikely to be sufficient to treat inflammatory arthritis, but current drugs that inhibit FAK may inhibit multiple factors, which could increase their efficacy in rheumatoid arthritis.
滑膜成纤维细胞侵入软骨和骨，导致类风湿性关节炎中的关节破坏。然而，调节滑膜成纤维细胞侵袭的机制尚未完全明确。粘着斑激酶（FAK）在多种细胞类型的细胞侵袭中发挥作用，并且FAK抑制剂正处于癌症治疗的临床试验阶段。关于FAK在炎性关节炎中的作用知之甚少，但是鉴于其在滑膜组织中的表达、其在其他细胞侵袭中的已知作用以及FAK抑制剂潜在的临床可用性，确定FAK是否促成滑膜成纤维细胞侵袭和炎性关节炎非常重要。
用FAK抑制剂处理后，使用基质胶侵袭小室测定人类风湿滑膜成纤维细胞的侵袭能力。分别通过Transwell测定法和荧光明胶降解的显微镜检查，评估FAK抑制的类风湿滑膜成纤维细胞中细胞侵袭的两个组成部分，即迁移和局部基质降解。使用可诱导敲除fak的肿瘤坏死因子α（TNFα）诱导性关节炎小鼠，如上所述测定FAK缺陷型小鼠关节炎滑膜成纤维细胞的侵袭和迁移，并对FAK缺陷型小鼠的关节炎进行临床和病理评分。
抑制人类风湿滑膜成纤维细胞中的FAK会损害细胞侵袭和迁移。局部基质降解发生在中央和粘着斑处，后者是滑膜成纤维细胞中基质降解的新位点，但FAK抑制剂对降解没有影响。FAK缺失减少了小鼠关节炎滑膜成纤维细胞的侵袭，但不影响迁移或TNFα诱导的关节炎严重程度和关节侵蚀。
FAK抑制剂可减少滑膜成纤维细胞的侵袭和迁移，但滑膜成纤维细胞迁移和TNFα诱导的关节炎并不依赖于FAK本身。因此，单独抑制FAK不太可能足以治疗炎性关节炎，但目前抑制FAK的药物可能会抑制多种因子，这可能会增加它们在类风湿性关节炎中的疗效。
