Campagnuolo Giuseppe, Bolon Brad, Feige Ulrich
Amgen, Inc., Thousand Oaks, California 91320-1789, USA.
Arthritis Rheum. 2002 Jul;46(7):1926-36. doi: 10.1002/art.10369.
To assess the effect of different dosages and treatment schedules of osteoprotegerin (OPG) on joint preservation in an experimental model of adjuvant-induced arthritis (AIA).
Male Lewis rats with AIA (6-8 per group) were treated with a subcutaneous bolus of recombinant human OPG according to one of the following schedules: daily OPG (an efficacious regimen) starting at disease onset (days 9-15), early intervention (days 9-11), delayed intervention (days 13-15), and extended therapy (days 9-22). Inflammation (hind paw swelling) was quantified throughout the clinical course; osteoporosis (bone mineral density [BMD], by quantitative dual x-ray absorptiometry) and morphologic appraisals of inflammation, bone damage, intralesional osteoclasts (by semiquantitative histopathologic scoring), and integrity of the articular cartilage matrix (by retention of toluidine blue stain) were determined in histology sections of arthritic hind paws.
OPG provided dose- and schedule-dependent preservation of BMD and periarticular bone while essentially eliminating intralesional osteoclasts. Dosages > or = 2.5 mg/kg/day preserved or enhanced BMD and prevented essentially all erosions. A dosage of 4 mg/kg/day protected joint integrity to a comparable degree when given for 7 (days 9-15) or 14 (days 9-22) consecutive days. At this dosage, early intervention (days 9-11) was twice as effective as delayed intervention (days 13-15) at preventing joint dissolution. Erosions and osteoclast scores were greatly decreased for 26 days (measured from the first treatment) after 7 or 14 daily doses of OPG (4 mg/kg/day). OPG treatment also prevented loss of cartilage matrix proteoglycans, an indirect consequence of protecting the subchondral bone. No OPG dosage or regimen alleviated weight loss, inflammation, or periosteal osteophyte production.
These data indicate that OPG preserves articular bone and (indirectly) articular cartilage in arthritic joints in a dose- and schedule-dependent manner, halts bone erosion when given at any point during the course of arthritis, produces sustained antierosive activity after a short course, and is most effective when initiated early in the disease.
在佐剂诱导性关节炎（AIA）实验模型中，评估骨保护素（OPG）不同剂量和治疗方案对关节保护的效果。
将患有AIA的雄性Lewis大鼠（每组6 - 8只）按照以下方案之一给予皮下注射重组人OPG：疾病发作时（第9 - 15天）每日注射OPG（一种有效方案）、早期干预（第9 - 11天）、延迟干预（第13 - 15天）以及延长治疗（第9 - 22天）。在整个临床过程中对炎症（后爪肿胀）进行量化；通过定量双能X线吸收法测定骨质疏松（骨矿物质密度[BMD]），并在患关节炎后爪的组织学切片中对炎症、骨损伤、病灶内破骨细胞（通过半定量组织病理学评分）以及关节软骨基质完整性（通过甲苯胺蓝染色保留情况）进行形态学评估。
OPG以剂量和方案依赖的方式保护BMD和关节周围骨，同时基本消除病灶内破骨细胞。剂量≥2.5mg/kg/天可维持或提高BMD，并基本预防所有侵蚀。当连续给予7天（第9 - 15天）或14天（第9 - 22天）时，4mg/kg/天的剂量在保护关节完整性方面效果相当。在此剂量下，早期干预（第9 - 11天）在预防关节溶解方面的效果是延迟干预（第13 - 15天）的两倍。在每日给予7或14剂OPG（4mg/kg/天）后26天（从首次治疗开始测量），侵蚀和破骨细胞评分大幅降低。OPG治疗还可预防软骨基质蛋白聚糖的丢失，这是保护软骨下骨的间接结果。没有OPG剂量或方案能减轻体重减轻、炎症或骨膜骨赘形成。
这些数据表明，OPG以剂量和方案依赖的方式保护关节炎关节中的关节骨和（间接）关节软骨，在关节炎病程中的任何时间给予均可阻止骨侵蚀，短疗程后产生持续的抗侵蚀活性，且在疾病早期开始时最为有效。
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