Current concepts in the biology of orthodontic tooth movement.

Adaptive biochemical response to applied orthodontic force is a highly sophisticated process. Many layers of networked reactions occur in and around periodontal ligament and alveolar bone cells that change mechanical force into molecular events (signal transduction) and orthodontic tooth movement (OTM). Osteoblasts and osteoclasts are sensitive environment-to-genome-to-environment communicators, capable of restoring system homeostasis disturbed by orthodontic mechanics. Five micro-environments are altered by orthodontic force: extracellular matrix, cell membrane, cytoskeleton, nuclear protein matrix, and genome. Gene activation (or suppression) is the point at which input becomes output, and further changes occur in all 5 environments. Hundreds of genes and thousands of proteins participate in OTM. Gene-directed protein synthesis, modification, and integration form the essence of all life processes, including OTM. Bone adaptation to orthodontic force depends on normal osteoblast and osteoclast genes that correctly express needed proteins at the right times and places. Cell membrane receptor-ligand docking is an important initiator of signal transduction and a discovery target for new bone-enhancing drugs. Despite progress in identification of regulatory molecules, the genetic mechanism of "orchestrated synthesis" between different cells, tissues, and systems remains largely unknown. Interpatient variation in mechanobiological response is most likely due to differences in periodontal ligament and bone cell populations, genomes, and protein expression patterns. Discovery of mutations in OTM-associated genes of orthodontic patients, including those regulating osteoclast bone-matrix acidification, chloride channel function, and osteoblast-derived mineral and protein matrices, will permit gene therapy to restore normal matrix and protein synthesis and function. Achieving selectivity in targeting abnormal genes, cells, and tissues is a major obstacle to safe and effective clinical application of gene engineering and stem-cell mediated tissue growth. Orthodontic treatment is likely to evolve into a combination of mechanics and molecular-genetic-cellular interventions: a change from shotgun to tightly focused communication with OTM cells.