Abstract
The overgrowth of synovial tissues is critical in the pathogenesis of rheumatoid arthritis (RA). The expression of Synoviolin (SYN), an E3 ubiquitin ligase, is upregulated in arthritic synovial fibroblasts and is involved in the overgrowth of synovial cells during RA. However, the molecular mechanisms involved in the elevated SYN expression are not known. Here, we found that SYN expression is elevated in the synovial fibroblasts from mice with collagen-induced arthritis (CIA). The proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-α (TNF-α) induce SYN expression in mouse synovial fibroblasts. Cultivation of mouse synovial fibroblasts with IL-1β activates mitogen-activated protein kinases, including extra-cellular signal-regulated kinase (Erk), JNK (c-Jun N-terminal kinase), and p38, while only Erk-specific inhibitor blocks IL-1β-induced SYN expression. Expression of transcription factor ETS1 further enhances IL-1β-induced SYN expression. The dominant negative ETS1 mutant lacking the transcription activation domain inhibits SYN expression in a dose-dependent manner. The activation of both Erk1/2 and ETS1 is increased in the CIA synovial fibroblasts. Inhibition of Erk activation reduces ETS1 phosphorylation and SYN expression. Our data indicate that the proinflammatory cytokines IL-1β and TNF-α induce the overgrowth of synovial cells by upregulating SYN expression via the Erk1/-ETS1 pathway. These molecules or pathways could therefore be potential targets for the treatment of RA.
Highlights
Rheumatoid arthritis (RA) is a chronic debilitating disease of the joints characterized by leukocyte infiltration, hyperproliferation of synovial cells, and bone destruction
This process requires a cascade of AP-1 = activator protein-1; CFA = complete Freund's Adjuvant; CIA = collagen-induced arthritis; DMEM = Dulbecco's modified Eagle's medium; EBS = ETS binding site; ER = endoplasmic reticulum; extra-cellular signal-regulated kinase (Erk) = extracellular signal-regulated kinase; ETS1-DN = dominant negative mutant of ETS1; FBS = fetal bovine serum; GST = glutathione S-transferase; IACUC = institutional animal care and use committee; IL = interleukin; Jun N-terminal kinase (JNK) = c-Jun Nterminal kinase; MAPK = mitogen-activated protein kinase; NF-κB = nuclear factor-kappa B; NP-40 = Nonidet P-40; PCR = polymerase chain reaction; RA = rheumatoid arthritis; RT-PCR = reverse transcription-polymerase chain reaction; SYN = Synoviolin; TNF-α = tumor necrosis factor-α; Ubc = ubiquitin-conjugation enzyme
Based on previous studies that have suggested that Erk may activate ETS1 transcription activity [30] together with our findings that Erk and ETS1 are involved in IL-1β-induced SYN expression, we proposed that IL-1β induces SYN expression in mouse synovial fibroblasts via the Erk-ETS1 pathway
Summary
Rheumatoid arthritis (RA) is a chronic debilitating disease of the joints characterized by leukocyte infiltration, hyperproliferation of synovial cells, and bone destruction. Ubiquitination is a process that covalently conjugates ubiquitin to the target protein for degradation This process requires a cascade of AP-1 = activator protein-1; CFA = complete Freund's Adjuvant; CIA = collagen-induced arthritis; DMEM = Dulbecco's modified Eagle's medium; EBS = ETS binding site; ER = endoplasmic reticulum; Erk = extracellular signal-regulated kinase; ETS1-DN = dominant negative mutant of ETS1; FBS = fetal bovine serum; GST = glutathione S-transferase; IACUC = institutional animal care and use committee; IL = interleukin; JNK = c-Jun Nterminal kinase; MAPK = mitogen-activated protein kinase; NF-κB = nuclear factor-kappa B; NP-40 = Nonidet P-40; PCR = polymerase chain reaction; RA = rheumatoid arthritis; RT-PCR = reverse transcription-polymerase chain reaction; SYN = Synoviolin; TNF-α = tumor necrosis factor-α; Ubc = ubiquitin-conjugation enzyme
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
