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siRNA targeting Timp1 accelerates tooth movement and alleviates relapse in mice

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Dept. of Orthodontics/박사
The common presenting problems of the long duration of treatment and posttreatment relapse still lose simple and effective solutions during orthodontic procedure. Periodontal soft-tissue is one of the key points to both problems. It is known that as a tooth moves through the gingiva, the response of the gingiva is to increase collagen formation to resist this movement. The primary factor causing relapse in orthodontically rotated teeth is the displaced supra-alveolar connective tissue fibers. Surgically cutting the circumferential supracrestal fibers called circumferential supracrestal fiberotomy (CSF) is known as a means of accelerating the kinetics of tooth movement and reducing the tendency to relapse. So far CSF is the unique technique demonstrating advantages both in tooth movement and relapse, however, as an invasive procedure, low patient acceptability suggests that an alternative approach is required. The matrix metalloproteinases (MMPs), a group of zinc-dependent endopeptidases, contribute to the cleavage of various components of the extracellular matrix (ECM), and activate osteoclasts to trigger bone resorption. The expression levels of MMPs and tissue inhibitors of metalloproteinase (Timps) are increased at both the resorption and apposition sides during tooth movement. It is postulated that the alteration of MMPs/Timps balance regulates ECM degradation. As far as is known, delivering Timp1 siRNA to rat with hepatic fibrogenesis resulted in indirect types I and III collagen fibrolysis by elevating the expression and activity of MMP-13, which is the main substrate of Timp1. Timp1 could inhibit almost all MMPs, except MT1-MMP, MT3-MMP, MT5-MMP and MMP-19. Based on the above, Timp1 is proposed as a potential therapeutic intervention target for tooth movement and relapse. RNAi offers researchers an effortless tool for the interrogation of the biological mechanism, and will likely work as a standard therapeutic agent in illness treatment by selectively silencing genes. In this study, the possibility and potential mechanism of Timp1 siRNA in attenuating the collagen expression was assessed in vitro first, using a NIH3T3 cell culture. The Timp1 and collagen1 productions were tested by RT-PCR and western blot. Then the effects on tooth movement and relapse were judged after local subperiosteum Timp1 siRNA injection in a mouse tooth movement model induced by a Ni-Ti closed coil spring. Timp1 siRNA efficiently inhibited Timp1 expression and decreased collagen1 protein level by ~70% after transfection for 48-72 h in vitro. The maximum mean amount of tooth movement in the transfection group and control group on 17 days was 0.94 mm and 0.73 mm, respectively. 80% of the accelerated tooth movement was apparent during the early activation period, between days 0 and 7. During two weeks relapse phase, the relapse percentage of Timp1 siRNA group was 15.96%, significantly less than 64.38% in the control group. This study indicated that Timp1 siRNA and any other medicine which could modify the homeostasis between Timps and MMPs may be a potential pharmacological agent for enhancing tooth movement and inhibiting relapse simultaneously.
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