Intron retention in PI‐PLC γ1 mRNA as a key mechanism affecting MMP expression in human primary fibroblast‐like synovial cells

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. Significant Statement This manuscript focuses on the modulation of phosphoinositide‐specific phospholipase C (PI‐PLC) γ1 in human primary fibroblast‐like synoviocytes, which leads to the modulation of metalloprotease‐3 (MMP‐3), MMP‐13, and ADAMTS‐5, involved in the degradation of extracellular matrix in degenerative joint diseases. We found that in some synoviocyte samples, the PI‐PLC γ1 mRNA incurs in the intron retention (IR) phenomenon, which results in an unsuccessful translation of the proteins associated with the decrease of MMP enzymes. Moreover, IR is increased after cell treatment with Harpagophytum procumbens extract (HPE), traditionally used to treat osteoarthritis. Considering that HPE results are effective in modulating MMPs only in synoviocyte samples where the IR phenomenon is present, it is necessary to evaluate individual variability in the personalized medicine field.