Role of mast cells and their modification by drugs on a disease model for rheumatoid arthritis.

为了阐明肥大细胞（MC）在类风湿性关节炎（rheumatoid arthritis，RA）模型雄性DBA/1 J小鼠的牛II型胶原（CII）诱导的关节炎（CIA）病理过程中的作用，研究了克罗埃宁钠2种口服前药的作用。将前药应用于CII免疫的小鼠7或8周，在第一次免疫后第6周明显出现CIA后开始。这两种药物每天服用一次。关节炎症状评分在未治疗的免疫小鼠中显著升高，并且评分的升高被前药治疗抑制。放射学评分或指骨破坏也得到改善的前药。病理组织学观察和血清IgG型抗CII抗体滴度测量也表明前药的改善。血清白细胞介素6在未处理的免疫小鼠中较高，并且升高被前药处理抑制。在未治疗的免疫小鼠中，关节炎或相应区域中的MC数量增加，并且前药治疗降低了这种增加。然后，通过免疫组织化学方法研究前药对CIA小鼠指关节中基质金属蛋白酶（MMP）-2，-3和-9表达的影响。MMP-2、MMP-3和MMP-9在滑膜、软骨和软骨-血管翳连接处的免疫染色程度和强度均受到显著抑制。总之，口服应用的MC稳定剂的前药对类风湿性关节炎模型具有功效。MC数量与关节炎症状以及前药作用的显著相关性表明MC在关节炎发病机制中的重要作用。

To clarify the role of mast cells (MCs) in pathological process of bovine type II collagen (CII)-induced arthritis (CIA) of male DBA/1J mice, which is a model for rheumatoid arthritis, effects of 2 kinds of oral deliverable prodrug of cromolyn sodium were examined. The prodrugs were applied to CII-immunized mice for 7 or 8 weeks, starting after the apparent occurrence of CIA in week 6 after the first immunization. Both drugs were applied once a day. Symptomatic scores of arthritis elevated significantly in non-treated immunized mice, and the elevation of scores was inhibited by prodrugs-treatment. Radiographic scores or phalangeal destruction were also improved by the prodrugs. Pathohistological observation and serum IgG type anti-CII antibody titers measurement also indicated improvement by the prodrugs. Serum interleukin 6 was higher in non-treated immunized mice, and the elevation was inhibited by a prodrug-treatment. MCs number in arthritic or corresponding region was increased in non-treated immunized mice and the increase was reduced by the prodrugs-treatment. Then, the effects of a prodrug on matrix metalloproteinase (MMP)-2, -3 and -9 expression by immunohistochemistry in finger joints of CIA mice were investigated. The extent and intensity of immunostaining of MMP-2, -3 and -9 was dramatically suppressed in synovium, cartilage and cartilage-pannus junction. In conclusion, orally applied prodrugs of a MC stabilizer have an efficacy on rheumatoid arthritis model. Significant correlation of MCs numbers and arthritis symptoms as well as effects of the prodrugs suggests the significant role of MCs in the pathogenesis of arthritis.