Mesenchymal Stem Cells Enhance Therapeutic Effect and Prevent Adverse Gastrointestinal Reaction of Methotrexate Treatment in Collagen-Induced Arthritis

Abstract

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.

Differentially expressed miRNAs in bone after methotrexate treatment

“…Additionally, we have further shown that expression of key adipocytic genes C/EBPα and PPARγ considerably increased, indicating the adipogenic responses after MTX treatment. Our results support previous investigations (Fan et al, 2012; Georgiou et al, 2012; Marques et al, 2013; Zhai et al, 2021). Regulatory roles of miRNAs involved in controlling osteogenesis and adipogenesis have been studied under many pathological conditions (e.g., menopause and osteoporosis), however miRNAs that might be involved in MTX‐induced bone defects have not been characterized (H. G. Zhang et al, 2019; X. Zhang et al, 2018).…”

Long‐term passages of human clonal mesenchymal stromal cells can alleviate the disease in the rat model of collagen‐induced arthritis resembling early passages of different heterogeneous cells

“…Cytokine shifts play key roles in inflammation, synovial hyperplasia, and cartilage and bone destruction; hence, decreases in inflammatory cytokine levels and elevated levels of anti‐inflammatory cytokines can reduce clinical symptoms of arthritis (Shu et al., 2015; Zhai et al., 2021). We investigated the level of pro‐ and anti‐inflammatory cytokines in the sera of the rat RA model.…”

Changes of macrophage and CD4+ T cell in inflammatory response in type 1 diabetic mice

“…In the process of inflammation, M1 macrophages secrete IL-6 and IL-1β 50 . M2 macrophages secrete IL-10 and produce an anti-inflammatory microenvironment 51 . Therefore, we measured the ratio of M1/M2 macrophages in mouse kidneys using the Flow cytometry method.…”