Shikonin attenuates rheumatoid arthritis by targeting SOCS1/JAK/STAT signaling pathway of fibroblast like synoviocytes

Abstract

Background Rheumatoid arthritis is a progressive and systemic autoimmune disease seriously compromises human health. Fibroblast like synoviocytes are the major effectors of proliferation and inflammation in rheumatoid arthritis synovial tissue. Shikonin has anti-inflammatory and immunomodulatory activities. But, its role on synovitis of rheumatoid arthritis is unknown. Methods The DBA/1 male mice were randomly divided into the following three groups (n = 6): (1) the normal control group of mice, (2) the CIA (collagen-induced arthritis) group in which mice suffered from arthritis induced by collagen, (3) the SKN (shikonin) group of mice which got arthritis and given intragastrically with shikonin 4 mg/kg per day continuously for 20 days,(4) the MTX (methotrexate) group of mice which got arthritis and orally administration with shikonin 0.5 mg/kg once two days continuously for 20 days. The therapeutic effect of shikonin on collagen induced arthritis mice was tested by arthritis incidence rate, arthritis score and inflammatory joint histopathology. The invasion, adhesion and migration of fibroblast like synoviocytes induced by tumor necrosis factor-α were applied to measure the anti-synovitis role of shikonin. The effect of shikonin on expression of interleukin-6, interleukin-1β and tumor necrosis factor-α was measured by enzyme linked immunosorbent assay. The interaction between shikonin and suppressor of cytokine signaling 1 was verified by molecular docking. The signaling pathways activated by shikonin were measured by western blot. Results Shikonin decreased the arthritis score and arthritis incidence, and inhibited inflammation of inflamed joints in collagen induced arthritis mice. And shikonin reduced the number of vimentin+cells in collagen induced arthritis mice inflamed joints. Meanwhile, shikonin suppressed tumor necrosis factor-α-induced invasion, adhesion and migration of fibroblast like synoviocytes and reduced the expression of interleukin-6, interleukin-1β and tumor necrosis factor-α. And we found that shikonin targeted suppressor of cytokine signaling 1. More interestingly, shikonin blocked the phosphorylation of Janus kinase 1/signal transducer andactivator of transcription 1/signal transducer andactivator of transcription 6 in synovial tissues and in fibroblast like synoviocytes. Conclusion Shikonin represents a promising new anti-rheumatoid arthritis drug candidate that has anti-synovitis effect in collagen induced arthritis mice and inhibits tumor necrosis factor-α-induced fibroblast like synoviocytes by targeting suppressor of cytokine signaling 1/ Janus kinase/signal transducer andactivator of transcription signaling pathway. These findings demonstrate that shikonin has anti-synovitis effect and has great potential to be a new drug for the treatment of rheumatoid arthritis.

Elevated fatty acid β-oxidation by leptin contributes to the proinflammatory characteristics of fibroblast-like synoviocytes from RA patients via LKB1-AMPK pathway

“…RA-FLS invasive characteristics are related to a series of pathological processes, such as overproliferation, release of proinflammatory mediators, interactions with immune and nonimmune cells, direct or indirect joint destruction [27][28][29]. It is demonstrated that lipid metabolism can promote breast cancer stemness and chemoresistance [19].…”

Forsythiaside A exhibits anti‐migration and anti‐inflammation effects in rheumatoid arthritis in vitro model

“…In addition, Chikusetsusaponin IVa targets the JAK/STAT signaling pathway to exhibit anti‐inflammatory and osteoprotective effects in RA 28 . Shikonin modulates the SOCS1/JAK/STAT signaling pathway to improve RA progression 29 . Besides, lncRNA ZNF667‐AS1 accelerates the JAK/STAT pathway to alleviate RA progression 30 .…”

Osthole regulates N6‐methyladenosine‐modified TGM2 to inhibit the progression of rheumatoid arthritis and associated interstitial lung disease

“…Detailed histopathological scores of arthritis severity were blindly measured by experimenters as described in our previous study. 10 …”

“…After the mice were euthanized, the joints, lungs, livers, kidneys, and serum of the mice were harvested for H&E staining, immunofluorescence, immunohistochemistry, and enzyme‐linked immunosorbent assay (ELISA). Detailed histopathological scores of arthritis severity were blindly measured by experimenters as described in our previous study 10 …”

“…In the past few decades, more and more natural compounds have exhibited their efficiency in treating RA. 9 Our previous studies also demonstrated several natural compounds, such as sarsasapogenin, 5 shikonin, 10 and celastrol, 11 that served as potential anti‐RA drugs. Osthole (OS) is an active ingredient that could be extracted from Cnidium , Angelica , and Citrus plants with low cost and presented anti‐inflammatory 12 , 13 , 14 and immunosuppressive activities 15 , 16 in human diseases.…”