In vivo RANK signaling blockade using the receptor activator of NF-κB:Fc effectively prevents and ameliorates wear debris-induced osteolysis via osteoclast depletion without inhibiting osteogenesis
In vivo RANK signaling blockade using the receptor activator of NF-κB:Fc effectively prevents and ameliorates wear debris-induced osteolysis via osteoclast depletion without inhibiting osteogenesis
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DOI：
10.1359/jbmr.2002.17.2.192
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发表时间：
2002-02-01
影响因子：
6.2
通讯作者：
Schwarz, EM
中科院分区：
文献类型：
--
作者：
Childs, LM;Paschalis, EP;Schwarz, EM
（P）由于磨损碎屑引起的骨溶解导致的置换失败仍然是全关节置换术的主要临床问题和最大限制。基于我们对破骨细胞参与这一过程的了解以及破骨细胞生成和骨吸收中NF-κ B受体激活剂（RANK）信号传导的需求，我们在小鼠颅骨模型中研究了RANK阻断剂预防和改善钛（Ti）诱导的骨质溶解的疗效。与安慰剂对照组相比，我们发现，每48小时腹膜内（ip）给予1 mg/kg以上剂量的RANK：Fc可显著抑制局部植入Ti后的破骨细胞生成和骨吸收。在10 mg/kg ip/48 h下发生完全抑制，产生的结果在统计学上等同于Ti给药RANK-/-小鼠获得的数据。我们还评价了第5天RANK：Fc单次注射对已建立的骨质溶解的影响，发现Ti处理的多核抗酒石酸酸性磷酸酶阳性（TRAP（+））细胞在16天后仍然耗尽。更重要的是，这种破骨细胞消耗不影响骨形成，因为在第5天从骨质溶解中损失的骨在第21天恢复。分别通过钙黄绿素标记和红外（IR）显微镜对这些颅骨中新形成骨的数量和质量进行评估，结果显示RANK：Fc处理无显著负面影响。这些研究表明，通过RANK阻断的破骨细胞耗竭是预防和逆转磨损碎屑诱导的骨质溶解的有效方法，而不会危及骨生成。
(P)rosthesis failure due to wear debris-induced osteolysis remains a major clinical problem and the greatest limitation for total joint arthroplasty. Based on our knowledge of osteoclast involvement in this process and the requirements of receptor activator of NF-kappaB (RANK) signaling in osteoclastogenesis and bone resorption, we investigated the efficacy of RANK blockade in preventing and ameliorating titanium (Ti)-induced osteolysis in a mouse calvaria model. Compared with placebo controls we found that all doses of RANK:Fc above 1 mg/kg intraperitoneally (ip) per 48 h significantly inhibited osteoclastogenesis and bone resorption in response to Ti implanted locally. Complete inhibition occurred at 10 mg/kg ip per 48 h, yielding results that were statistically equivalent to data obtained with Ti-treated RANK-/- mice. We also evaluated the effects of a single injection of RANK:Fc on day 5 on established osteolysis and found that Ti-treated were still depleted for multinucleated tartrate-resistant acid phosphatase-positive (TRAP(+)) cells 16 days later. More importantly, this osteoclast depletion did not affect bone formation because the bone lost from the osteolysis on day 5 was restored by day 21. An assessment of the quantity and quality of the newly formed bone in these calvariae by calcein labeling and infrared (IR) microscopy, respectively, showed no significant negative effect of RANK:Fc treatment. These studies indicate that osteoclast depletion via RANK blockade is an effective method to prevent and reverse wear debris-induced osteolysis without jeopardizing osteogenesis.