Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease involving excessive inflammation. Recently, RA associated with a metabolic disorder was revealed to be non-responsive to RA medications. Metformin has been reported to have a therapeutic effect on RA and obesity. The aim of this investigation was to study the therapeutic effect and the underlying mechanism of metformin's action in an experimental model of collagen-induced arthritis (CIA) associated with obesity. Metformin was administered daily for 13 weeks to mice with CIA that had been fed a high-fat diet. Metformin ameliorated the development of CIA in obese mice by reducing autoantibody expression and joint inflammation. Furthermore, metformin decreased the expression levels of pSTAT3 and pmTOR and had a small normalizing effect on the metabolic profile of obese CIA mice. In addition, metformin increased the production of pAMPK and FGF21. Metformin also induced the differentiation of brown adipose tissue (BAT), which led to a reciprocal balance between T helper (Th) 17 and regulatory T (Treg) cells in vitro and in vivo. These results suggest that metformin can dampen the development of CIA in obese mice and reduce metabolic dysfunction by inducing BAT differentiation. Thus, metformin could be a therapeutic candidate for non-responsive RA.
Highlights
Rheumatoid arthritis (RA), a progressive and systemic form of autoimmune arthritis, is characterized by chronic inflammation and the infiltration of synovial immune cells into the affected joints
The anti-inflammatory profile of metformin-treated mice Consistent with the arthritis score, minimal signs of inflammation were detected in the metformin-treated obese collagen-induced arthritis (CIA) mice, whereas extensive infiltration of immune cells was observed in vehicle- and Enbrel-treated obese CIA mice
Histological analyses showed that joint destruction, bone and cartilage damage, and pannus formation were ameliorated in the metformin-treated obese CIA mice compared to vehicle- or Enbrel-treated obese CIA mice (Figure 2a)
Summary
Rheumatoid arthritis (RA), a progressive and systemic form of autoimmune arthritis, is characterized by chronic inflammation and the infiltration of synovial immune cells into the affected joints It has been well-documented that several proinflammatory cytokines are involved in the pathogenesis of RA and exacerbate its progression.[1] there have been advances in the therapeutic functions of RA drugs, the treatment of RA remains extremely difficult.[2,3] a significant proportion of RA patients (30–40%) have no response to RA drugs such as anti-tumor necrosis factor (TNF)-α antibody therapy (such as infliximab).[4,5] Currently, RA patients who show no response to RA drugs are more susceptible to non-response to other biologics used to treat RA.[6] It has recently been reported that the probability of nonresponse to RA treatment is associated with metabolic disorders.[7] Obesity, a metabolic disorder that plays a key role in the inflammatory response, leads to the upregulation of proinflammatory cytokine expression. It has been demonstrated that there is in increase in the expression of proinflammatory cytokines and a parallel decrease in the expression of anti-inflammatory cytokines among obese individuals compared to healthy lean individuals.[8,9] obesity is associated with inflammatory and autoimmune diseases, increasing the possibility of diseases such as RA occurring in obese people.[10,11]
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