Arthritis Research UK Pain Centre, University of Nottingham, Nottingham, UK.
School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
Ann Rheum Dis. 2014 Aug;73(8):1558-65. doi: 10.1136/annrheumdis-2013-203260. Epub 2013 May 30.
Increased subchondral bone turnover may contribute to pain in osteoarthritis (OA).
To investigate the analgesic potential of a modified version of osteoprotegerin (osteoprotegerin-Fc (OPG-Fc)) in the monosodium iodoacetate (MIA) model of OA pain.
Male Sprague Dawley rats (140-260 g) were treated with either OPG-Fc (3 mg/kg, subcutaneously) or vehicle (phosphate-buffered saline) between days 1 and 27 (pre-emptive treatment) or days 21 and 27 (therapeutic treatment) after an intra-articular injection of MIA (1 mg/50 µl) or saline. A separate cohort of rats received the bisphosphonate zoledronate (100 µg/kg, subcutaneously) between days 1 and 25 post-MIA injection. Incapacitance testing and von Frey (1-15 g) hind paw withdrawal thresholds were used to assess pain behaviour. At the end of the study, rats were killed and the knee joints and spinal cord removed for analysis. Immunohistochemical studies using Iba-1 and GFAP quantified levels of activation of spinal microglia and astrocytes, respectively. Joint sections were stained with haematoxylin and eosin or Safranin-O fast green and scored for matrix proteoglycan and overall joint morphology. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts were quantified. N=10 rats/group.
Pre-emptive treatment with OPG-Fc significantly attenuated the development of MIA-induced changes in weightbearing, but not allodynia. OPG-Fc decreased osteoclast number, inhibited the formation of osteophytes and improved structural pathology within the joint similarly to the decrease seen after pretreatment with the bisphosphonate, zoledronate. Therapeutic treatment with OPG-Fc decreased pain behaviour, but did not improve pathology in rats with established joint damage.
Our data suggest that early targeting of osteoclasts may reduce pain associated with OA.
骨软骨下骨转换增加可能导致骨关节炎（OA）疼痛。
研究一种改良型护骨素（护骨素-Fc（OPG-Fc））在单碘乙酸（MIA）OA 疼痛模型中的镇痛潜力。
雄性 Sprague Dawley 大鼠（140-260g）在关节内注射 MIA（1mg/50μl）或生理盐水后第 1 天至第 27 天（预防性治疗）或第 21 天至第 27 天（治疗性治疗）接受 OPG-Fc（3mg/kg，皮下注射）或载体（磷酸盐缓冲盐水）治疗。另一组大鼠在 MIA 注射后第 1 天至第 25 天接受双膦酸盐唑来膦酸（100μg/kg，皮下注射）治疗。使用测痛仪和 von Frey（1-15g）后爪撤回阈值评估疼痛行为。研究结束时，处死大鼠并取出膝关节和脊髓进行分析。使用 Iba-1 和 GFAP 进行免疫组织化学研究，分别定量评估脊髓小胶质细胞和星形胶质细胞的激活水平。关节切片用苏木精和伊红或番红 O 快速绿染色，并对基质蛋白聚糖和关节整体形态进行评分。定量分析抗酒石酸酸性磷酸酶阳性破骨细胞的数量。N=10 只大鼠/组。
预防性给予 OPG-Fc 可显著减轻 MIA 诱导的体重变化，但不能减轻所有痛觉过敏。OPG-Fc 减少破骨细胞数量，抑制骨赘形成，并改善关节内结构病理学，与双膦酸盐唑来膦酸预处理后观察到的效果相似。治疗性给予 OPG-Fc 可减轻疼痛行为，但不能改善已建立的关节损伤大鼠的病理学。
我们的数据表明，早期靶向破骨细胞可能会减轻与 OA 相关的疼痛。
