Abstract
ObjectivePeriploca forrestii Schltr has been used as a Chinese folk medicine for the treatment of rheumatism, arthralgia and fractures. However, the anti-arthritic activity of Periploca forrestii saponin (PFS) and the active compound has still not been revealed. This study aimed to investigate the protective effects and mechanisms of PFS on collagen type II (CII) collagen-induced arthritis (CIA) mice. We sought to investigate whether PFS and Periplocin could regulate osteoclastogenesis, and if so, further investigation on its mechanism of action.MethodsArthritis was induced in female BALB/c mice by CIA method. PFS was administered at a dose of 50 mg/kg body weight once daily for five weeks. The effects of treatment in mice were assessed by histological and biochemical evaluation in sera and paws. Anti-osteoclastogenic action of PFS and Periplocin was identified using an osteoclast formation model induced by RANKL.ResultsPFS ameliorated paw erythema and swelling, inhibited bone erosion in ankle joint histopathological examination. PFS treatment resulted in decreased IgG2a, and increased IgG1 levels in the serum of CIA mice. Decreased TNF-α, and increased interleukin (IL)-4 and IL-22 levels were also found in PFS-treated mice. PFS inhibited the I-κBα phosphorylation, blocked nuclear factor (NF)-κB/p65 phosphorylation and abrogated AP-1/c-Fos activity. PFS downregulated toll-like receptor (TLR) 4, STAT3 and MMP-9 expression in CIA mice and RANKL-induced osteoclastogenesis. PFS and Periplocin inhibited RANKL-induced osteoclast formation in a dose dependent manner within nongrowth inhibitory concentration, and PFS decreased osteoclastogenesis-related marker expression, including cathepsin K and MMP-9.ConclusionThis study revealed that the protective mechanism of PFS on CIA was associated with regulatory effects on proinflammatory factors and further on the crosstalk between NF-κB and c-Fos/AP-1 in vivo and in vitro. Therefore, PFS is a promising therapeutic alternative for the treatment of RA, evidencing the need to conduct further studies that can identify their active components in treating and preventing RA.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease with 1% prevelance in industrialized countries
Decreased tumor necrosis factor (TNF)-α, and increased interleukin (IL)-4 and IL-22 levels were found in Periploca forrestii saponin (PFS)-treated mice
This study revealed that the protective mechanism of PFS on collageninduced arthritis (CIA) was associated with regulatory effects on proinflammatory factors and further on the crosstalk between nuclear factor-κ B (NF-κB) and cFos/activator protein-1 (AP-1) in vivo and in vitro
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease with 1% prevelance in industrialized countries. RA pathology is relevant to the immune system and skeletal system, its etiology and pathogenesis remain not entirely clear, and many cell types, such as fibroblasts, T cells, B cells, and osteoclasts (OCs), have been implicated These inflammatory cells infiltrate the synovium and are further activated to release many cytokines, autoantibodies, and matrix metalloproteinases (MMPs), leading to cartilage and bone destruction [1]. Pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-6, IL-1β and interferon (IFN)-γ play significant roles in mediating joint inflammation [2,3] These cytokines are expressed in the arthritic synovium in RA and induce the expression of receptor activator of nuclear factor kappa B ligand (RANKL). The activation of these transcription factors directly stimulates the expression of a number of osteoclastogenesis-specific genes, including Tartrate-resistant acid phosphatase (TRAP), MMP-9, NFATc1 and cathepsin K, leading to osteoclast differentiation and bone resorption [6, 7]
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