Single vs. repeated matrix metalloproteinase-13 knockdown with intra-articular short interfering RNA administration in a murine osteoarthritis model

Purpose: Our aims were 1) to estimate the duration of short interfering RNA (siRNA) effect on matrix metalloproteinase-13 (Mmp-13) levels by a single intra-articular injection using a mouse knee osteoarthritis (OA) model and 2) to test whether repeated injections results in any additional suppressive effect on cartilage degradation compared to a single injection. Materials and Methods: OA was induced in 9weeks old male C57BL/6 mice by destabilization of medial meniscus (DMM). Chemically modified siRNA targeted for Mmp-13 was injected into the knee joint at 1 week post-DMM surgery. Control group of knees received that for non-targeted genes. Synovial tissue was collected to measure Mmp-13 expression levels by quantitative polymerase chain reaction (qPCR) at 2, 3, and 6weeks after surgery in each group. To test the effect of multiple injections, we created four experiment groups according to the number of injections. Histological assessment of articular cartilage was performed at 8weeks post-DMM surgery. Results: In the Mmp-13 siRNA-treated group, expression levels of Mmp-13 mRNA were decreased by 40% compared to the control group at 2weeks after surgery (p=0.04), before returning to baseline at 3 weeks after surgery. A significant improvement in the histological score was observed in all Mmp-13 siRNA-treated groups compared to the control group (p<0.05). However, no significant differences were seen between the single and multiple injection group. Conclusions: Our results suggested that the duration of siRNA effect in the knee joint lasts for at least 1week, and that no further benefit is achieved by multiple injections.