Abstract
It is generally believed that some inflammatory antigens can recognize Toll-like receptors on synovial fibroblasts (SFs) and then activate downstream signals, leading to the formation of RASFs and inducing rheumatoid arthritis (RA). The objective of the current work was to study on the hypothesis that outer PAMP (LPS) binds to the inner DAMP (HMGB1) and becomes a complex that recognizes TLRs/RAGE on SFs, thus initiating a signaling cascade that leads to the secretion of inflammatory cytokines and chemokines, production of tissue-destructive enzymes, and formation of RASFs, finally resulting in RA. Osteoarthritis synovial fibroblasts (OASFs) were co-cultured with HMGB1–LPS complex in vitro for five generations to induce the transformation of human SFs to RA-like SFs (tOASFs). Then, changes of tOASFs in cell cycle and apoptosis–autophagy balance were investigated in vitro, and the pathogenicity of tOASFs was evaluated in a SCID mouse model in vivo. In vitro cell cycle analysis showed more tOASFs passing through the G1/S checkpoint and moving to S or G2 phase. Flow cytometry and confocal microscopy showed that apoptosis was reduced and autophagy was enhanced significantly in tOASFs as compared with those in OASFs. The expression of certain receptors and adhesion molecules in tOASFs was upregulated. In vivo experiments showed that tOASFs attached to, invaded, and degraded the co-implanted cartilage. In addition, histochemistry showed excessive proliferation of tOASFs and the expression of matrix metalloproteinases (MMPs). Based on the above findings, we conclude that HMGB1–LPS complex could promote the formation of RASFs.
Highlights
Infections may contribute to the onset of Rheumatoid arthritis (RA), for example, patients with periodontal disease have been shown to have a higher prevalence of RA than patients without periodontitis, and several virulence factors, including the bacterial lipopolysaccharides (LPS), toxins, and hemagglutinins of the main pathogen—P. gingivalis, may have a role in the pathogenesis of RA.[4,5] Group A streptococcal cell wall peptidoglycan– polysaccharide complexes can induce acute inflammation of the peripheral joints resulting in chronic erosive arthritis in susceptible rats,[6,7] which indicates that microorganism components can induce the onset of RA
We further showed that the expression of certain receptors was upregulated in to RA-like SFs (tOASFs), including TLR2, TLR4, and receptor for advanced glycation end products (RAGE), and the adhesion molecules ICAM-1 and VCAM-1
Many studies have demonstrated that excessive proliferation and invasive growth of RASFs are attributed to impaired regulation of the cell cycle and imbalance between survival and death.[10,11]
Summary
Infections may contribute to the onset of RA, for example, patients with periodontal disease have been shown to have a higher prevalence of RA than patients without periodontitis, and several virulence factors, including the bacterial lipopolysaccharides (LPS), toxins, and hemagglutinins of the main pathogen—P. gingivalis, may have a role in the pathogenesis of RA.[4,5] Group A streptococcal cell wall peptidoglycan– polysaccharide complexes can induce acute inflammation of the peripheral joints resulting in chronic erosive arthritis in susceptible rats,[6,7] which indicates that microorganism components can induce the onset of RA. Pathological study[8] showed synovial thickening and excessive proliferation of SFs, suggesting that the HMGB1–pathogen-associated molecular pattern (PAMP) complex might induce the formation of RASFs. In the current study, osteoarthritis synovial fibroblasts. HMGB1–LPS complex promotes SF transformation Y Qin et al (OASFs) were isolated from the tissue obtained during reconstructive surgery and co-cultured with HMGB1–LPS complex in vitro for 5–7 generations to induce the transformation of normal SFs to RA-like SFs (tOASFs). Histochemistry further showed excessive proliferation of tOASFs and the expression of MMPs. In vitro cell cycle analysis showed more tOASFs passing through the G1/S checkpoint and moving to S or G2 phase. We have proved that HMGB1–LPS complex could promote the formation of RA-like transformed SFs
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