Central Research Laboratory, Research & Development Division, Seikagaku Corporation, Tateno 3-1253, Higashiyamato-shi, Tokyo, 207-0021, Japan.
BMC Musculoskelet Disord. 2024 Nov 29;25(1):975. doi: 10.1186/s12891-024-08083-9.
Knee osteoarthritis (KOA) is the most common type of joint disease in elderly people and is characterized by pain and dysfunction. Although the monoiodoacetate (MIA)-induced model is widely used as a rodent KOA model, it is important to acknowledge the inherent limitations of this model, as the MIA model develops complex pathological phases on a daily basis. An accurate understanding of this model and the selection of an appropriate time point according to the target for drug candidates can lead to the development of clinically effective drugs.
Changes in the pathological state of the MIA model were assessed via histopathological evaluation. Clodronate, a bisphosphonate, and diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), were selected as models of clinically effective drugs due to their different mechanisms of action. The analgesic effects of both drugs on the MIA model were evaluated. The long-term effect of clodronate on subchondral bone osteoclasts was also evaluated.
Histopathological evaluation revealed that MIA-induced symptomatic behavior occurred in the early and late phases and was accompanied by synovial inflammation and osteoclast-related joint degeneration, respectively. Although clodronate inhibited symptomatic behavior and prevented cartilage degeneration from the early to late phases, diclofenac inhibited symptomatic behavior only in the early phase. Clodronate acted locally and inhibited the activation of subchondral osteoclasts.
Pathological changes, such as synovial changes in the early phase and knee joint degeneration in the late phase, in the MIA model are similar to those in human KOA. Our results indicate that the early phase in the MIA model is appropriate for evaluating the effects of anti-inflammatory agents such as NSAIDs and corticosteroids. The late phase in the MIA model is appropriate for evaluating the effects of drugs that act on cartilage and subchondral bone.
膝骨关节炎（KOA）是老年人最常见的关节疾病，其特征为疼痛和功能障碍。虽然单碘乙酸盐（MIA）诱导模型被广泛用于建立啮齿类动物 KOA 模型，但需要认识到该模型存在固有局限性，因为 MIA 模型在每天都会发展出复杂的病理阶段。准确了解该模型，并根据药物候选物的目标选择合适的时间点，可促成开发出具有临床疗效的药物。
通过组织病理学评估来评估 MIA 模型的病理状态变化。氯膦酸盐（双膦酸盐）和双氯芬酸（非甾体抗炎药）被选为具有临床疗效的药物模型，因为它们具有不同的作用机制。评估了这两种药物对 MIA 模型的镇痛作用。还评估了氯膦酸盐对软骨下骨破骨细胞的长期作用。
组织病理学评估显示，MIA 诱导的症状性行为发生在早期和晚期，分别伴有滑膜炎和破骨细胞相关的关节退化。虽然氯膦酸盐在早期至晚期均抑制症状性行为并预防软骨退化，但双氯芬酸仅在早期抑制症状性行为。氯膦酸盐发挥局部作用并抑制软骨下骨破骨细胞的激活。
MIA 模型中的滑膜变化等早期病理变化和膝关节退化等晚期病理变化与人类 KOA 相似。我们的结果表明，MIA 模型的早期阶段适合评估非甾体抗炎药和皮质类固醇等抗炎药物的效果。MIA 模型的晚期阶段适合评估作用于软骨和软骨下骨的药物的效果。
