H Force Keygen Download 13
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In this study, we have demonstrated that H3K27me3-binding protein JMJD3 is induced in response to aberrant mechanical forces and targeted ablation of JMJD3 relieves the aberrant force-induced OA pathogenesis. Then we further investigated the function of JMJD3 in mechanical force-related OA and its possible mechanisms. The results showed that the overexpression of JMJD3 induced aberrant force-related OA pathogenesis in vitro and in vivo. Our study also confirmed that JMJD3 specifically regulated aberrantly increased H3K27me3 levels at NR4A1 promoter and decreased NR4A1 transcription activity. In addition, the disturbance of JMJD3 by gene knockout or administration of its inhibitor GSK-J4 alleviated the aberrant force-induced OA pathogenesis. Therefore, we speculated that the regulatory role of JMJD3 in aberrant force-related OA pathogenesis can be achieved by demethylating H3K27me3 at the NR4A1 promoter.
Several points should be emphasized. First, although JMJD3 has been suggested to be a key epigenetic regulator, the underlying mechanisms and the functional roles of H3K27me3 in response to aberrant mechanical forces remain unknown. Second, although JMJD3 has been reported to be a H3K27me3 demethylase, the specific demethylase activity of JMJD3 in the nucleus of chondrocytes was unknown. Furthermore, whether this demethylase activity is required for NR4A1 repression or not and the specific binding motif for NR4A1 remain to be determined. Third, although our study demonstrated a critical role of H3K27me3 in aberrant force-related OA pathogenesis, many other histone modifications still remain to be investigated. Fourth, although we demonstrated that administration of GSK-J4 or siRNA against JMJD3 attenuated the aberrant force-induced OA pathogenesis, the effects of such treatment in vivo still remained to be determined.
The current study, although still with limited evidence, provides a novel epigenetic regulatory mechanism in mechanical force-related OA pathogenesis and suggests the potential of targeting JMJD3 for OA therapy.
In this work, we mainly focus on the potential role of histone demethylase JMJD3 in aberrant force-induced chondrocyte injury. JMJD3 was found to be upregulated in FSS-induced chondrocyte apoptosis. The epigenetic regulator JMJD3 was hypothesized to have a regulatory function in FSS-induced chondrocyte apoptosis as a result of the demethylation of H3K27me3. Finally, we confirmed that FSS induces a dynamic change in the distribution of H3K27me3 at the promoter of NR4A1. In addition, JMJD3 was shown to be involved in the aberrant force-related OA pathogenesis in vitro and in vivo. Our findings clearly indicated that JMJD3 is a potential epigenetic regulator in OA and that the combined use of JMJD3 inhibitor or sh-JMJD3 can alleviate aberrant force-induced chondrocyte injury. Further study may provide a novel strategy for epigenetic therapies for OA.
Z. L. and L. W. conceived the idea, designed the study, and wrote the manuscript; H. X., Y. L., M. L., and J. Z. analyzed the data; C. Z. and Z. J. performed the experiments. All authors have read and approved the manuscript. 827ec27edc