Abstract
Rheumatoid arthritis (RA) is a disorder triggered by autoimmune reactions and related with chronic inflammation and severe disability. Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs) have shown a hopeful immunomodulatory effect towards repairing cartilage and restoring joint function. Additionally, indomethacin (IMC), a nonsteroidal compound, has been considered as a potent therapeutic agent that exhibits significant antipyretic properties and analgesic effects. The target of the current research is to assess the antiarthritic efficacy of BM-MSCs (106 cells/rat at 1, 6, 12 and 18 days) and IMC (2 mg/kg body weight/day for 3 weeks) either alone or concurrently administered against complete Freund's adjuvant-induced arthritic rats. Changes in paw volume, body weight, gross lesions, and antioxidant defense system, as well as oxidative stress, were assessed. The Th1 cytokine (IL-1β) serum level and Th2 cytokine (IL-4) and Nrf-2 ankle joint expression were detected. In comparison to normal rats, it was found that the CFA-induced arthritic rats exhibited significant leukocytosis and increase in paw volume, LPO level, RF, and IL-1β serum levels. In parallel, arthritic rats that received BM-MSCs and/or IMC efficiently exhibited decrease in paw edema, leukocytosis, and enhancement in the antioxidant enzymatic levels of SOD, GPx, GST, and GSH in serum besides upregulation of Nrf-2 and anti-inflammatory IL-4 expression levels in the ankle articular joint. Likewise, these analyses were more evidenced by the histopathological sections and histological score. The data also revealed that the combined administration of BM-MSC and IMC was more potent in suppressing inflammation and enhancing the anti-inflammatory pathway than each agent alone. Thus, it can be concluded that the combined therapy with BM-MSC and IMC may be used as a promising therapeutic choice after assessing their efficacy and safety in human beings with RA, and the antiarthritic effects may be mediated via modulatory effects on Th1/Th2 cytokines, ozidative stress, and Nrf-2.
Highlights
Rheumatoid arthritis (RA) is a predominant inflammatory disorder that is accompanied by a relapsing and remitting course of joint inflammation and synovitis, swelling, autoantibody production, bone dysfunction, and cartilage degradation [1]
Rats of all arthritic groups developed arthritis after Complete Freund’s adjuvant (CFA) induction. e CFAinduced arthritic rats exhibited significant (P < 0.05) increase in paw volume maintained for 21 days when compared with the normal group (Figure 1)
Edema and redness of the right hind paw and ankle joint acted as external measures for determining the severity of the arthritic inflammatory model. e CFA-induced arthritic control group displayed gradual decrease in both of them following Bone Marrow-derived Mesenchymal Stem Cells (BM-mesenchymal stem cells (MSCs)) and/or IMC treatments (Figure 2)
Summary
Rheumatoid arthritis (RA) is a predominant inflammatory disorder that is accompanied by a relapsing and remitting course of joint inflammation and synovitis, swelling, autoantibody production, bone dysfunction, and cartilage degradation [1]. RA is accompanied with systemic and additional extraarticular complications of some organs including the lungs and heart. Such systemic manifestations reduce the quality of life and are responsible for disability, Evidence-Based Complementary and Alternative Medicine early mortality, and socioeconomic costs [2]. The pathogenesis of RA is unknown; several etiological causes have been involved such as genetic, as well as environmental, factors, infectious agents, heat shock proteins, and sex hormones. Such causes, by themselves, are insufficient to explain the etiology [5]. There is no optimal therapy for RA except for systemic immune suppressants
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