Inhibition of transient receptor potential canonical 6 attenuates fibroblast-like synoviocytes mediated synovial inflammation and joint destruction in rheumatoid arthritis.

OBJECTIVES: We aimed to define the importance of transient receptor potential canonical 6 (TRPC6) expression and function in fibroblast-like synoviocytes (FLSs) and to investigate the contribution of TRPC6 in the model of rheumatoid arthritis (RA). METHODS: We compared TRPC6 expression levels in FLSs from RA patients (RA-FLSs), and in FLSs from osteoarthritis (OA) patients (OA-FLSs). By using vitro functional assays which united with small interfering RNA-induced knockdown and functional modulation of TRPC6 in RA-FLSs. Finally, we confirmed the effectiveness of regulating TRPC6 in a collagen induced arthritis (CIA) mice model. RESULTS: We found that FLSs expressed the TRPC6 as their major Transient receptor potential canonical channel. Both mRNA and protein expression of TRPC6 were found somewhat higher levels in RA-FLSs than in OA-FLSs. Moreover, inhibiting expression of TRPC6 in vitro reduced proliferation of, as well as inflammatory mediator and protease production by, RA-FLSs, whereas opening native TRPC6 enhanced both proliferation and inflammatory mediator of RA-FLSs. Additionally, a TRPC6 deficiency in mice blunted the development of experimental RA, CIA models, reduced joint and bone damage, and inhibited FLS invasiveness and proliferation. CONCLUSIONS: Our results demonstrated a critical role of TRPC6 in regulating FLSs mediated inflammation. Therefore, TRPC6 represents potential therapeutic targets in RA.

TREM-2 negatively regulates LPS-mediated inflammatory response in rat bone marrow-derived MSCs.

To the best of our knowledge, our previous study demonstrated the expression of triggering receptor expressed on myeloid cells 2 (TREM­2) in human bone marrow mesenchymal stem cells (MSCs) for the first time. However, the inflammation regulatory role of TREM­2 in MSCs remain elusive. The aim of the present study was to investigate the immune regulation and the underlying mechanism of TREM­2 in rat bone marrow MSCs. MSCs were divided into three groups: NullMSCs, TREM­2MSCs, and NormMSCs. TREM­2 was expressed in MSCs at the mRNA and protein level. Following stimulation by lipopolysaccharide (LPS), the gene transcription levels of TREM­2 and inflammatory cytokines were increased. The expression levels of inflammatory cytokines, including tumor necrosis factor­α (TNF­α) and interleukin­1ß (IL­1ß), in the TREM­2MSCs lentiviral vector group were significantly downregulated, and the expression of IL­10 was significantly upregulated compared with the controls. Western blot analysis revealed that TREM­2 downregulated the LPS­induced inflammatory response in MSCs, which was probably associated with regulating AKT serine/threonine kinase and p38 mitogen­activated protein kinase downstream signaling proteins. The results of the current study demonstrated that TREM­2 negatively regulates the LPS­mediated inflammatory response in MSCs suggesting that TREM­2 is a potential target of immune regulation in rat MSCs.