MMP-9 inhibition suppresses wear debris-induced inflammatory osteolysis through downregulation of RANK/RANKL in a murine osteolysis model
MMP-9 inhibition suppresses wear debris-induced inflammatory osteolysis through downregulation of RANK/RANKL in a murine osteolysis model
复制标题
在小鼠骨质溶解模型中，MMP-9 抑制通过下调 RANK/RANKL 抑制磨损碎片诱导的炎症性骨质溶解
DOI：
10.3892/ijmm.2012.1145
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发表时间：
2012-12-01
影响因子：
5.4
通讯作者：
Cheng, Tao
中科院分区：
文献类型：
--
作者：
Chen, Desheng;Zhang, Xianlong;Cheng, Tao
人工关节置换术后，人工关节周围组织因磨损碎屑导致骨溶解及无菌性松动是一个严重的问题。基质金属蛋白酶-9（MMP-9）在松动的笔式种植体组织周围的破骨细胞中表达，但MMP-9在磨损碎屑诱导的骨质溶解中作用的分子机制仍不明确。我们使用小鼠骨质溶解模型来检验MMP-9抑制剂的给药降低核因子-κ B受体活化剂（RANK）和核因子-κ B配体（RANKL）的表达，从而抑制碎片诱导的炎性骨质溶解的假设。实验在3组15只小鼠中进行：对照组、钛（Ti）组和钛加四环素组。为了引起炎性骨质溶解，从同系同窝出生的动物中植入颅骨，然后将钛颗粒注射到除对照组外的所有组的已建立的气囊中。每日通过腹膜内（i. p.）注射，并且通过腹膜内注射向对照组和Ti组施用PBS。在骨-Ti植入后14天处死小鼠。收集具有完整骨植入物的袋膜用于组织学和分子分析。四环素对MMP-9和肿瘤坏死因子-α（TNF-α）的表达影响最小，但它降低了基因活化并抑制了RANK和RANKL的表达，从而抑制了钛颗粒诱导的炎性骨质溶解。四环素减少了袋组织中抗酒石酸酸性磷酸酶（TRAP）阳性细胞的数量。我们在小鼠骨质溶解模型中的结果表明，通过下调RANK/RANKL，四环素显著抑制碎片诱导的炎性骨质溶解。它在临床实践中的使用可能有助于预防接受全关节置换术的患者发生并发症。
Wear debris-induced osteolysis in periprosthetic tissue with aseptic loosening is a serious problem after total joint arthroplasty. Matrix metalloproteinase-9 (MMP-9) is expressed in osteoclast cells that surround loosening pen-implant tissue, but the molecular mechanism of MMP-9 action in wear debris-induced osteolysis remains ambiguous. We used a murine osteolysis model to examine the hypothesis that administration of an MMP-9 inhibitor reduces the expression of receptor activator of nuclear factor-kappa B (RANK) and nuclear factor-kappa B ligand (RANKL) and, thereby, suppresses-debris-induced inflammatory osteolysis. Experiments were performed in 3 groups of 15 mice: a control, a titanium (Ti) and a Ti plus tetracycline group. To provoke inflammatory osteolysis, calvarial bone was implanted from syngeneic littermates, followed by injection of Ti particles into established air pouches for all groups except the control. Tetracycline was administered daily by intraperitoneal (i.p.) injection, and PBS was administered by i.p. injection to the control and Ti groups. Mice were sacrificed 14 days after bone-Ti implantation. Pouch membranes with the intact bone implants were collected for histological and molecular analysis. Tetracycline had minimum effect on the expression of MMP-9 and tumor necrosis factor-alpha (TNF-alpha) but it decreased gene activation and inhibited the expression of RANK and RANKL, thereby inhibiting Ti-particle-induced inflammatory osteolysis. Tetracycline decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive cells in the pouch tissues. Our results in the murine osteolysis model suggest that through the downregulation of RANK/RANKL, tetracycline significantly inhibits debris-induced inflammatory osteolysis. Its use in clinical practice may help prevent complications experienced by patients who have undergone total joint arthroplasty.