title: 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.
authors.affiliation: Department of Laboratory Diagnosis, Changhai Hospital of the Second Military Medical University, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Laboratory Diagnosis, Changhai Hospital of the Second Military Medical University, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, Xinhua Hospital, Shanghai, China.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, Changhai Hospital of the Second Military Medical University, Shanghai, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Laboratory Diagnosis, Changhai Hospital of the Second Military Medical University, Shanghai, China.
authors.forename: G
authors.initials: G
authors.lastname: Tang
authors.affiliation: Department of Laboratory Diagnosis, Changhai Hospital of the Second Military Medical University, Shanghai, China.
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Diagnosis, Changhai Hospital of the Second Military Medical University, Shanghai, China.
authors.forename: Z
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Rheumatology and Immunology, Changzheng Hospital of the Second Military Medical University, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Rheumatology and Immunology, Changhai Hospital of the Second Military Medical University, Shanghai, China.
authors.forename: S-M
authors.initials: SM
authors.lastname: Dai
authors.affiliation: Department of Laboratory Diagnosis, Changhai Hospital of the Second Military Medical University, Shanghai, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Shen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001343:Autophagy / Q000187:drug effects; D002356:Cartilage / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D024243:HMGB1 Protein / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011971:Receptors, Immunologic / Q000187:drug effects / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D013997:Time Factors
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D016207:Cytokines; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; D020782:Matrix Metalloproteinases