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ABSTRACT
We tested whether orthodontic tooth movement (OTM) could be blocked by local administration of echistatin or an arginine-glycine-aspartic acid (RGD) peptide, agents known to perturb bone remodeling, adjacent to maxillary molars in rats. These molecules were incorporated into ethylenevinyl acetate (ELVAX), a non-biodegradable, sustained-release polymer. In vitro experiments showed that the echistatin and RGD peptide were released from ELVAX in active forms at levels sufficient to disrupt osteoclasts. Biotinylated RGD peptide was released from ELVAX into the PDL after surgical implantation. ELVAX loaded with either RGD peptide or echistatin and surgically implanted next to the maxillary molars inhibited orthodontic tooth movement (p < 0.01). The RGD peptide also reduced molar drift (p < 0.05). This study shows the feasibility of using ELVAX to deliver integrin inhibitors adjacent to teeth to limit local tooth movement in response to orthodontic forces.
KEY WORDS: integrins, orthodontic tooth movement, echistatin, RGD.
Received July 9, 2002; Last revision May 23, 2003; Accepted June 6, 2003
INTRODUCTION
Histological examination of the alveolar bone has demonstrated that, during orthodontic tooth movement (OTM), alveolar bone modeling (apposition of bone on its surface to shape and size it) predominates on the tension side, and alveolar bone remodeling (activation of osteoclast precursors, then osteoelastic bone resorption followed by bone formation to repair the defect) predominates on the pressure side (King et al., 1991b). The kinetics of OTM occurs in three phases: the initial tipping phase (activation of cells), a lag phase (recruitment of osteoclasts to the site, which starts to resorb bone), and finally the post-lag phase, where tooth movement occurs (Reitan, 1967).
Integrins have been directly linked to the cellular response to mechanical strain (Schwartz and Ingber, 1994). Both osteoclasts (the bone-resorbing cells) and osteoblasts (the bone-forming cells) express multiple integrins and bind many RGD-containing proteins, including osteopontin and cleaved type I collagen, which are abundant in bone (Teitelbaum, 2000). Agents such as echistatin, an RGD-containing peptide derived from snake venom, and short RGD-peptides interfere with aspects of integrin-mediated signal transduction, which are important for bone remodeling. Echistatin can induce the disruption of cell-matrix interactions and appears to cause an early reduction of pp125^sup FAK^ phosphorylation. This results in the disassembly of actin cytoskeleton and of focal adhesions (Staiano et al.,...