Schwarz E M, Benz E B, Lu A P, Goater J J, Mollano A V, Rosier R N, Puzas J E, Okeefe R J
Department of Medicine, University of Rochester Medical Center, New York 14642, USA.
J Orthop Res. 2000 Nov;18(6):849-55. doi: 10.1002/jor.1100180602.
Individuals who suffer from severe joint destruction caused by the various arthritidies often undergo total joint arthroplasty. A major limitation of this treatment is the development of aseptic loosening of the prosthesis in as many as 20% of patients. The current paradigm to explain aseptic loosening proposes that wear debris generated from the prosthesis initiates a macrophage-mediated inflammatory response by resident macrophages, leading to osteoclast activation and bone resorption at the implant interface. No therapeutic interventions have been proved to prevent or inhibit aseptic loosening. The development of therapeutic strategies is limited due to the absence of a quantitative surrogate in which drugs can be screened rapidly in large numbers of animals. We have previously described a model in which titanium particles implanted on mouse calvaria induce an inflammatory response with osteolysis similar to that observed in clinical aseptic loosening. Here, we present new methods by which the osteolysis in this model can be quantified. We determined that 6-8-week-old mice in normal health have a sagittal suture area of 50 (+/-6) microm2, which contains approximately five osteoclasts. As a result of the titanium-induced inflammation and osteolysis, the sagittal suture area increases to 197 (+/-27) microm2, with approximately 30 osteoclasts, after 10 days of treatment. The sagittal suture area and the number of osteoclasts in the calvaria of sham-treated mice remained unchanged during the 10 days. We also determined the effects of pentoxifylline, a drug that blocks the responses of tumor necrosis factor-alpha to wear debris, and the osteoclast inhibitor alendronate. We found that both drugs effectively block wear debris-induced osteolysis but not osteoclastogenesis. In conclusion, we found the measurements made with this model to be reproducible and to permit quantitative analysis of agents that are to be screened for their potential to prevent aseptic loosening.
患有各种关节炎导致严重关节破坏的个体通常会接受全关节置换术。这种治疗方法的一个主要局限性是，多达20%的患者会出现假体无菌性松动。目前用于解释无菌性松动的范例提出，假体产生的磨损颗粒会引发驻留巨噬细胞介导的炎症反应，导致破骨细胞活化和植入物界面处的骨吸收。尚未证明有任何治疗干预措施可预防或抑制无菌性松动。由于缺乏一种可在大量动物中快速筛选药物的定量替代指标，治疗策略的开发受到限制。我们之前描述了一种模型，其中植入小鼠颅骨的钛颗粒会引发类似于临床无菌性松动中观察到的伴有骨溶解的炎症反应。在此，我们介绍了可对该模型中的骨溶解进行量化的新方法。我们确定，健康的6 - 8周龄小鼠的矢状缝面积为50（±6）平方微米，其中约有五个破骨细胞。经过10天的治疗，由于钛诱导的炎症和骨溶解，矢状缝面积增加到197（±27）平方微米，破骨细胞约有30个。在10天内，假手术处理小鼠颅骨的矢状缝面积和破骨细胞数量保持不变。我们还确定了己酮可可碱（一种阻断肿瘤坏死因子-α对磨损颗粒反应的药物）和破骨细胞抑制剂阿仑膦酸盐的作用。我们发现这两种药物均能有效阻断磨损颗粒诱导的骨溶解，但不能阻断破骨细胞生成。总之，我们发现该模型所进行的测量具有可重复性，并允许对用于筛选预防无菌性松动潜力的药物进行定量分析。
