Abstract
A series of experiments have been carried out to investigate the effects of different concentrations of thapsigargin (0, 0.001, 0.1, and 1 μM) on the proliferation and survival of human rheumatoid arthritis synovial cells (MH7A). The results showed that thapsigargin can block the cell proliferation in human rheumatoid arthritis synovial cells in a time- and dose-dependent manner. Results of Hoechst staining suggested that thapsigargin may induce cell apoptosis in MH7A cells in a time- and dose-dependent manner, and the percentages of cell death reached 44.6% at thapsigargin concentration of 1 μM treated for 4 days compared to the control. The protein and mRNA levels of cyclin D1 decreased gradually with the increasing of thapsigargin concentration and treatment times. Moreover, the protein levels of mTORC1 downstream indicators pS6K and p4EBP-1 were reduced by thapsigargin treatment at different concentrations and times, which should be responsible for the reduced cyclin D1 expressions. Our results revealed that thapsigargin may effectively impair the cell proliferation and survival of MH7A cells. The present findings will help to understand the molecular mechanism of fibroblast-like synoviocytes proliferations and suggest that thapsigargin is of potential for the clinical treatment of rheumatoid arthritis.
Highlights
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of multiple joints, with disruption of joint cartilage
Higher concentrations of thapsigargin (0.1 μM and 1 μM) showed stronger inhibitory effect on cell replications than those in the control groups (Figure 1). These results suggested that thapsigargin may arrest cell proliferations in MH7A human rheumatoid arthritis synovial cells in a time- and dose-dependent manner
The results suggested that the mRNA levels of cyclin D1 were affected by thapsigargin treatment, and the changes of transcription levels were highly correlated with the quantitative changes of protein levels assayed in MH7A cells (Figure 3(c))
Summary
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of multiple joints, with disruption of joint cartilage. When the disease is unchecked, it leads to substantial disability and premature death. It affects approximately 0.8 percent of adults worldwide, is more common in women (by a ratio of 3 to 1), and has an earlier onset in women, frequently beginning in the childbearing years [1, 2]. An important characteristic of the rheumatoid synovium is the marked hyperplasia of the lining layer, which is caused by an increased number of fibroblastlike synoviocytes (FLSs) and macrophages. In RA synovium, FLSs, the major cell population in invasive pannus, actively participate in the inflammatory processes of RA [3, 4].
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