Combinatory Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Indomethacin on Adjuvant-Induced Arthritis in Wistar Rats: Roles of IL-1β, IL-4, Nrf-2, and Oxidative Stress

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.

Curcumin and Mesenchymal Stem Cells Ameliorate Ankle, Testis, and Ovary Deleterious Histological Changes in Arthritic Rats via Suppression of Oxidative Stress and Inflammation

“…RA, one of the most common chronic inflammatory autoimmune diseases, is distinguished by systemic inflammation, permanent synovitis, edema, and production of autoantibodies [ 45 ]. Because of their multipotent differentiation abilities, cell therapy using MSCs is the most common new technique in tissue repair and regeneration [ 14 , 15 , 32 , 46 ]. Additionally, MSCs have therapeutic potential to joint and bone diseases through the secretion of a number of immune modulating substances and cell-to-cell interactions leading to antiapoptotic, antifibrotic, immunosuppressive, and proangiogenic properties [ 47 ].…”

“…Curcumin has also been shown to inhibit many proinflammatory cytokines and mediators such as IL-1, IL-8, and nitric oxide synthase [ 48 ]. Consequently, curcumin's beneficial effects on inflammatory disorders are due to the suppression of immune functions of T-cells, specially Th1, which plays a key role in the pathogenesis of chronic inflammatory disorders such as arthritis ( Figure 10 ) [ 14 , 15 , 18 , 49 ].…”

“…TNF-α and other proinflammatory cytokines potentially amplify differentiation and activation of osteoclasts which in turn induce synovial hyperplasia, angiogenesis, cartilage erosion, and bone damage [11][12][13]. On the other hand, Th2 cytokines including IL-4 and IL-10 have anti-inflammatory effects, and their increases results in improving inflammation and arthritis [14,15].…”

“…The natural protection mechanism involves antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), as well as nonenzymatic antioxidant and reduced glutathione (GSH). The defect in such protective mechanism contributes to toxic oxidative free-radical accumulation and consequent degenerative changes [14,16]. Due to the adverse effects and toxicity arising from the use of antiarthritic drugs, more focus is placed in discovering safer, more efficient, natural product-based, alternative medicines with antioxidant activities [17][18][19].…”

“…In vivo , MSC immunoregulatory function has also been observed; treatment with MSCs in humans enhanced the outcome of allogeneic transplantation through reducing graft-versus-host disease (GVHD) and facilitating hematopoietic engraftment [ 28 ]. MSCs have been widely used in animal models to prevent the autoimmunity recurrence in lupus-pronounced mice [ 29 ], to promote improvement of experimental autoimmune encephalomyelitis [ 30 ], and to enhance amelioration of CFA-induced arthritis in rats [ 14 , 15 ]. Due to the success of MSC therapy in the treatment of some autoimmune disorders in animal models [ 30 ] and humans [ 28 ], the current research is aimed at examining the potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) either singly or in combination with curcumin in the therapy of RA in male and female Wistar rats.…”