Nonsteroidal Antiinflammatory Drugs and Prostaglandin E2 Modulate the Synthesis of Osteoprotegerin and RANKL in the Cartilage of Patients With Severe Knee Osteoarthritis
Nonsteroidal Antiinflammatory Drugs and Prostaglandin E2 Modulate the Synthesis of Osteoprotegerin and RANKL in the Cartilage of Patients With Severe Knee Osteoarthritis
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DOI：
10.1002/art.27204
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发表时间：
2010-02-01
影响因子：
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通讯作者：
Largo, Raquel
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文献类型：
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作者：
Moreno-Rubio, Juan;Herrero-Beaumont, Gabriel;Largo, Raquel
Objective.尽管骨保护素（OPG）/RANK/RANKL系统是骨重建的主要调节因子，但其在骨关节炎（OA）期间是否在软骨中受到调节仍不清楚。本研究的目的是检测非甾体类抗炎药（NSAID）治疗是否调节OA患者软骨中OPG和RANKL的合成，并研究前列腺素E-2（PGE（2））是否修饰培养的人OA软骨细胞中的该系统。在20例严重膝关节OA患者中进行了为期3个月的临床试验，所有患者均计划接受膝关节置换术。其中10名患者接受塞来昔布治疗，另外10名不愿接受治疗的患者作为对照组。手术后，软骨被处理用于分子生物学研究。我们还使用人OA软骨细胞检测PGE（2）对OPG/RANKL合成的影响，检测PGE（2）影响哪些表面受体。在OA患者中，塞来昔布减少软骨中RANKL的合成，从而增加OPG：RANKL的比值。在培养的人OA软骨细胞中，PGE（2）引起RANKL合成的剂量和时间依赖性增加，其程度大于OPG。共聚焦显微镜显示，PGE（2）诱导RANKL转运到细胞膜。只有EP 2/EP 4激动剂能复制PGE（2）对OPG和RANKL的诱导作用。长期NSAID治疗抑制软骨细胞合成的再吸收信号。在体外，PGE（2）通过关节软骨细胞调节这些骨代谢关键介质的表达和释放。OPG/RANK/RANKL在OA软骨代谢中的作用仍然未知，尽管这些蛋白质的合成将使软骨能够控制软骨下骨细胞的活性。
Objective. Although the osteoprotegerin (OPG)/RANK/RANKL system is the main modulator of bone remodeling, it remains unclear whether it is regulated in cartilage during osteoarthritis (OA). The aim of this study was to examine whether nonsteroidal antiinflammatory drug (NSAID) treatment modulates the synthesis of OPG and RANKL in the cartilage of patients with OA, and to investigate whether prostaglandin E-2 (PGE(2)) modifies this system in human OA chondrocytes in culture.Methods. A 3-month clinical trial was carried out in 20 patients with severe knee OA, all of whom were scheduled to undergo knee replacement surgery. Ten of these patients were treated with celecoxib, and the other 10 patients, who did not want to be treated, served as the control group. After surgery, cartilage was processed for molecular biology studies. We also used human OA chondrocytes to examine the effects of PGE(2) on OPG/RANKL synthesis, examining which surface receptors were affected by PGE(2).Results. In patients with OA, celecoxib decreased RANKL synthesis in the cartilage, thereby increasing the OPG: RANKL ratio. In human OA chondrocytes in culture, PGE(2) elicited a dose- and time-dependent increase in the synthesis of RANKL, the extent of which was greater than that of OPG. Confocal microscopy revealed that PGE(2) induced RANKL transport to the cell membrane. Only EP2/EP4 agonists reproduced the effects of PGE(2) on OPG and RANKL induction.Conclusion. Long-term NSAID treatment inhibited the resorptive signal synthesized by chondrocytes. In vitro, PGE(2) regulated the expression and release of these key mediators of bone metabolism by articular chondrocytes. The role of OPG/RANK/RANKL in OA cartilage metabolism is still unknown, although the synthesis of these proteins would enable the cartilage to control the activity of subchondral bone cells.