RANK/RANKL/OPG role in distraction osteogenesis

Distraction osteogenesis is a fundamental pillar for craniomaxillofacial reconstruction processes. Nonetheless, although the clinical, biomechanical, and histologic changes associated with distraction osteogenesis have been widely described, this is not the case with the molecular mechanisms that regulate bone synthesis in the interfragmentary gap resulting from the gradual separation of bone segments. Recent studies have attributed a decisive role to the RANK/RANKL/OPG system in regulating bone metabolism and osteoclastogenesis. Receptor activator of nuclear factor kappa beta (RANK), belonging to the tumor necrosis factor superfamily, is present in the osteoclasts. It promotes osteoclastogenesis when it binds to RANK ligand (RANKL), which is produced by the osteoblasts and other stromal cells. Osteoprotegerin (OPG) acts as a decoy receptor by binding to RANKL and preventing RANK signaling. Osteoclast activation is thus blocked and apoptosis induced. The aim of this review is to analyze the influence of the RANK/RANKL/OPG system on the bone healing and remodeling processes that occur in distraction osteogenesis, with a view to possibly developing molecular mechanisms that stimulate bone regeneration and inhibit resorption, thereby improving the clinical outcome for distraction osteogenesis.