Search

Ankylosing spondylitis is a male-predominant disease and previous study revealed that estrogens have an anti-inflammatory effect on the spondyloarthritis (SpA) manifestations in zymosan-induced SKG mice. This study aimed to evaluate the effect of selective estrogen receptor modulator (SERM) lasofoxifene (Laso) on disease activity of SpA. Mice were randomized into zymosan-treated, zymosan + 17β-estradiol (E2)-treated, and zymosan + Laso-treated groups. Arthritis was assessed by 18F-fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography/computed tomography and bone mineral density (BMD) was measured. Fecal samples were collected and 16S ribosomal RNA gene sequencing was used to determine gut microbiota differences. Both zymosan + E2-treated mice and zymosan + Laso-treated mice showed lower arthritis clinical scores and lower 18F-FDG uptake than zymosan-treated mice. BMD was significantly higher in zymosan + E2-treated mice and zymosan + Laso-treated mice than zymosan-treated mice, respectively. Fecal calprotectin levels were significantly elevated at 8 weeks after zymosan injection in zymosan-treated mice, but it was not significantly changed in zymosan + E2-treated mice and zymosan + Laso-treated mice. Gut microbiota diversity of zymosan-treated mice was significantly different from zymosan + E2-treated mice and zymosan + Laso-treated mice, respectively. There was no significant difference in gut microbiota diversity between zymosan + E2-treated mice and zymosan + Laso -treated mice. Laso inhibited joint inflammation and enhanced BMD in SKG mice, a model of SpA. Laso also affected the composition and biodiversity of gut microbiota. This study provides new knowledge regarding that selected SpA patients could benefit from SERM treatment. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the effects of CIP2A (Cancerous inhibitor of protein phosphatase 2A) on the apoptosis of RA FLS. Proliferation and apoptotic activity of RA FLS following treatment with CIP2A siRNA or control siRNA were analyzed using MTT assays and Cell Death Detection kit. RA FLS was treated with CIP2A siRNA or control siRNA in 3-, 6-, and 9-day intervals for a Western blot analysis to determine C-Myc expression. To evaluate the signal transduction pathways engaged in apoptosis, caspase-3 activity, caspase-9 activity, PARP, and phosphorylation of the Akt kinase were analyzed by Western blot. Cell viability of RA FLS was significantly lower in the CIP2A siRNA-treated group compared with the control after 7 days ( p = 0.022). Apoptosis of RA FLS was significantly higher in the CIP2A siRNA-treated group compared with the control when incubated for 3, 6, and 9 days ( p = 0.029, p = 0.021, p = 0.043, respectively). C-Myc expression did not change with the different incubation periods. CIP2A siRNA-treated FLS expressed higher level of activated caspase-3, caspase-9, and PARP ( p = 0.014, p = 0.020, p = 0.021, respectively) and lower level of phosphorylated Akt ( p = 0.001) compared with those treated with the control siRNA. Our data show that CIP2A expression in RA FLS is an important mediator of dysfunctional apoptosis independent of c-Myc stabilization. Expression of CIP2A may contribute to apoptotic resistance of RA FLS through the activation of Akt and deactivation of caspase-3, caspase-9, and PARP. Inhibition of CIP2A may therefore constitute a novel, promising therapeutic target in RA. [ABSTRACT FROM AUTHOR]