Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis
Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis
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DOI：
10.1002/art.34315
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发表时间：
2012-05-01
影响因子：
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通讯作者：
van den Berg, Wim B.
中科院分区：
文献类型：
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作者：
van Lent, Peter L. E. M.;Blom, Arjen B.;van den Berg, Wim B.
目的探讨Alarmins S100 A8和S100 A9在骨关节炎（OA）软骨破坏中的作用。方法比较两种不同的小鼠OA模型，其在滑膜活化方面不同。软骨破坏进行了组织学测量。关节炎患者的滑膜活检和血清样本来自髋关节队列和膝关节队列（CCN）的早期症状性关节炎患者。滑膜中介质的表达通过逆转录聚合酶链反应分析和免疫定位来测定。结果在胶原酶诱导的OA中，表现出明显的滑膜活化，白细胞介素-1 β仅在疾病的早期阶段以显著水平表达，而S100 A8和S100 A9表达在较长时间内（诱导后21天）保持高水平。在S100 A9基因敲除小鼠中，我们发现与野生型对照相比，S100 A8和S100 A9对滑膜活化（62%抑制）和OA软骨破坏（4573%抑制）有重大影响。相反，在手术诱导的不稳定内侧半月板模型中，滑膜参与很少，我们发现S100 A8和S100 A9在局灶性OA软骨破坏中没有作用。对早期症状性骨关节炎患者的关节镜滑膜活检样本进行检查，发现S100 A8和S100 A9信使RNA和蛋白质水平较高，与滑膜衬里厚度、内膜下细胞构成和关节破坏显著相关。在2年后关节破坏明显进展的患者中，S100 A8/A9血清蛋白水平在基线时显著升高（19%）。结论我们的数据表明，S100 A8和S100 A9蛋白在OA过程中的滑膜活化和软骨破坏中起关键作用，并且高水平可能预测OA患者的关节破坏。
Objective To investigate whether alarmins S100A8 and S100A9 are involved in mediating cartilage destruction during murine and human osteoarthritis (OA). Methods Two different murine models of OA that differed in terms of synovial activation were compared. Cartilage destruction was measured histologically. Synovial biopsy and serum samples from OA patients were derived from the Cohort Hip and Cohort Knee (CHECK) patients with symptomatic early OA. Expression of mediators in the synovium was measured by reverse transcriptionpolymerase chain reaction analysis and immunolocalization. Results In collagenase-induced OA, which showed marked synovial activation, interleukin-1 beta was expressed at significant levels only during the early stages of disease, whereas S100A8 and S100A9 expression remained high for a prolonged period of time (up to day 21 after induction). In S100A9-knockout mice, we found a major impact of S100A8 and S100A9 on synovial activation (62% inhibition) and OA cartilage destruction (4573% inhibition) as compared to wild-type controls. In contrast, in the surgically induced destabilized medial meniscus model, in which synovial involvement is scant, we found no role of S100A8 and S100A9 in the focal OA cartilage destruction. Examination of arthroscopic synovial biopsy samples from patients in the early symptomatic OA CHECK cohort revealed substantial levels of S100A8 and S100A9 messenger RNA and protein, which correlated significantly with synovial lining thickness, cellularity in the subintima, and joint destruction. Levels of S100A8/A9 serum protein were significantly enhanced (19%) at baseline in patients who had pronounced progression of joint destruction after 2 years. Conclusion Our data suggest that the S100A8 and S100A9 proteins are crucially involved in synovial activation and cartilage destruction during OA and that high levels may predict joint destruction in humans with OA.