Abstract：
The intron retention (IR) is a phenomenon utilized by cells to allow diverse fates at the same mRNA, leading to a different pattern of synthesis of the same protein. In this study, we analyzed the modulation of phosphoinositide-specific phospholipase C (PI-PLC) enzymes by Harpagophytum procumbens extract (HPE) in synoviocytes from joins of osteoarthritis (OA) patients. In some samples, the PI-PLC γ1 isoform mature mRNA showed the IR and, in these synoviocytes, the HPE treatment increased the phenomenon. Moreover, we highlighted that as a consequence of IR, a lower amount of PI-PLC γ1 was produced. The decrease of PI-PLC γ1 was associated with the decrease of metalloprotease-3 (MMP-3), and MMP-13, and ADAMTS-5 after HPE treatment. The altered expression of MMPs is a hallmark of the onset and progression of OA, thus substances able to decrease their expression are very desirable. The interesting outcomes of this study are that 35% of analyzed synovial tissues showed the IR phenomenon in the PI-PLC γ1 mRNA and that the HPE treatment increased this phenomenon. For the first time, we found that the decrease of PI-PLC γ1 protein in synoviocytes interferes with MMP production, thus affecting the pathways involved in the MMP expression. This finding was validated by the silencing of PI-PLC γ1 in synoviocytes where the IR phenomenon was not present. Our results shed new light on the biochemical mechanisms involved in the degrading enzyme production in the joint of OA patients, suggesting a new therapeutic target and highlighting the importance of personalized medicine.
摘要：
内含子保留（IR）是细胞利用的一种现象，可以在相同的mRNA上允许不同的命运，导致同一蛋白质合成的不同模式。在这项研究中,我们分析了骨关节炎（OA）患者关节滑膜细胞中Harpagophytumprocumbens提取物（HPE）对磷酸肌醇特异性磷脂酶C（PI-PLC）酶的调节。在一些样本中,PI-PLCγ1亚型成熟mRNA显示IR和，在这些滑膜细胞中，HPE处理增加了这种现象。此外，我们强调，作为IR的结果，产生较低量的PI-PLCγ1。PI-PLCγ1的降低与金属蛋白酶-3（MMP-3）的降低有关，HPE治疗后MMP-13和ADAMTS-5。MMPs表达的改变是OA发病和进展的标志,因此能够降低其表达的物质是非常理想的。这项研究的有趣结果是，35％的分析滑膜组织在PI-PLCγ1mRNA中显示出IR现象，并且HPE处理增加了这种现象。第一次,我们发现滑膜细胞中PI-PLCγ1蛋白的减少干扰了MMP的产生，从而影响参与MMP表达的途径。通过在不存在IR现象的滑膜细胞中沉默PI-PLCγ1来验证这一发现。我们的研究结果为OA患者关节中降解酶产生的生化机制提供了新的思路，提出了新的治疗目标，并强调了个性化医疗的重要性。
