HMGB1–LPS complex promotes transformation of osteoarthritis synovial fibroblasts to a rheumatoid arthritis synovial fibroblast-like phenotype

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.

Cilostazol inhibits HMGB1 release in LPS-activated RAW 264.7 cells and increases the survival of septic mice

“…IKKα and IKKβ are each critically important for the HMGB1-elicited chemotaxis of fibroblasts, macrophages, and neutrophils in vitro and of neutrophils in vivo [25]. Released HMGB1 also activates NF-κB, functioning in diverse roles in the pathophysiology of sepsis [26], arthritis [27][28][29], ischemia and reperfusion injury [27], and cancer [28]. Therefore, the inhibition of NF-κB activity by cilostazol can diminish the pathophysiological function of HMGB1 in sepsis.…”

PPAR-α Agonist WY-14643 Inhibits LPS-Induced Inflammation in Synovial Fibroblasts via NF-kB Pathway

“…Therefore, it is urgent to find out an efficient treatment for patients with OA by targeting the cells or molecules that regulate the pathological changes. There is increasing recognition that synovium become inflammatory in which synovial fibroblasts take an important role (Goldring et al 2015;Qin et al 2014), apart from the pathophysiological changes in cartilage and peri-articular bone (Pap et al 2015).…”

HMGB1 in health and disease

“…HMGB1-triggered joint inflammation is not mediated through the TNF-α pathway (Goldstein, 2008; Pullerits et al, 2008; Sundberg et al, 2008). HMGB1 forms complexes with IL-1α, IL-1β, and LPS to enhance immune and inflammatory responses at the joint (Qin et al, 2014; Wahamaa et al, 2011). Moreover, therapeutic targeting of HMGB1 (e.g., HMGB1 neutralizing antibodies, recombinant A box, recombinant thrombomodulin, soluble RAGE, oxaliplatin, gold salts, and glucocorticoid) inhibits HMGB1 release and activity, which prevents the progression of arthritis in experimental animals (af Klint et al, 2005; Bossaller and Rothe, 2013; Goldstein et al, 2007; Hamada et al, 2008; Ostberg et al, 2010; Ostberg et al, 2008; Takahashi et al, 2013b; Yuan et al, 2008; Zetterstrom et al, 2008).…”