Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by articular destruction and functional loss. Methotrexate (MTX) is effective in RA treatment. However, MTX induces several adverse events and 20%-30% of patients do not respond to MTX. Thus, it is urgent to enhance the therapeutic effects and reduce the side effects of MTX. Recent studies showed that mesenchymal stem cells (MSCs) were participants in anti-inflammation, immunoregulation, and tissue regeneration. However, whether the combined application of MSCs and MTX promotes the therapeutic effects and reduces the side effects of MTX has not been studied. In this study, we used bovine type II collagen to induce rheumatoid arthritis in mice (collagen-induced arthritis, CIA). Then, CIA mice were subjected to MTX or MSC treatment, or both. The therapeutic effect and adverse events of different treatments on RA were evaluated with micro-CT, HE staining, and immunohistochemistry in vivo. Apoptosis and proliferation of MODE-K cells were measured after treated with MTX or/and cocultured with UCs. To test M2 polarization, Raw264.7 macrophages were stimulated by MTX with different concentrations or cocultured with UCs. We found that the combined application of MSCs and MTX increased the therapeutic effects on RA, as evidenced by decreased arthritis score, inflammatory responses, and mortality. Moreover, in this combination remedy, MTX prefers to suppress inflammation by facilitating macrophage polarization to M2 type while UCs prefer to eliminate gastrointestinal side effects of MTX via mitigating the apoptosis of intestinal epithelial cells. Thus, a combination of MTX and UCs is a promising strategy for RA treatment.

中文翻译：

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间充质干细胞增强胶原蛋白诱发的关节炎的治疗效果并预防甲氨蝶呤治疗的胃肠道不良反应

类风湿关节炎（RA）是一种全身性自身免疫性疾病，其特征是关节破坏和功能丧失。甲氨蝶呤（MTX）在RA治疗中有效。但是，MTX会诱发一些不良事件，并且20％-30％的患者对MTX无反应。因此，迫切需要增强MTX的治疗效果并降低其副作用。最近的研究表明，间充质干细胞（MSCs）是抗炎，免疫调节和组织再生的参与者。然而，尚未研究MSC与MTX的组合应用是否促进治疗效果并降低MTX的副作用。在这项研究中，我们使用牛II型胶原蛋白在小鼠中诱发类风湿性关节炎（胶原蛋白诱发的关节炎，CIA）。然后，对CIA小鼠进行MTX或MSC处理，或两者。通过微CT，HE染色和体内免疫组织化学评估了不同治疗对RA的治疗效果和不良事件。用MTX处理或/和与UCs共培养后，测量MODE-K细胞的凋亡和增殖。为了测试M2极化，用不同浓度的MTX刺激Raw264.7巨噬细胞或与UCs共培养。我们发现，MSCs和MTX的联合应用增加了对RA的治疗效果，这可以通过降低关节炎评分，炎症反应和降低死亡率来证明。此外，在这种联合疗法中，MTX倾向于通过促进巨噬细胞极化为M2型来抑制炎症，而UCs则希望通过减轻肠道上皮细胞的凋亡来消除MTX的胃肠道副作用。从而，