Overloaded Orthopedic Force Induces Condylar Subchondral Bone Absorption by Stimulating Rat Mesenchymal Stem Cells Differentiating into Osteoclasts via mTOR-Regulated Secretion in Osteoblasts.

Appropriate orthopedic force led to bone remodeling of mandibular condyle, while overloaded orthopedic force (OOF) induced condylar bone absorption. Bone absorption is ascribed to the imbalanced activities between osteoclasts (OCs) and osteoblasts (OBs), mechanism of which remains unclear. This study aimed to observe the condylar changes induced by OOF by mandible advancement appliance and to further investigate the role of mammalian target of Rapamycin () and in osteoclastic differentiation of stem cells in vivo and in vitro. In vivo, the results of micro-CT analysis indicated that condylar bone resorption was induced by OOF through mandibular advancement appliance for 2 weeks and worsened time dependently. Morphologically, cartilage thickness was reduced, subchondral cortical bone line appeared not continuous, and subchondral bone exhibited irregular-shaped and owned uneven surface. The bone mineral density (BMD), bone volume/tissue volume (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th) were decreased accomplished with the increased trabecular separation (Tb.Sp) determined by micro-CT. In addition, based on immunofluorescent labeling, OOF activated both OCs and OBs, but osteoclastogenesis prevailed over osteogenesis. The activation and ratio of in OBs were elevated by OOF. In vitro, the results of western blot and polymerase chain reaction (PCR) consistently suggested that the and ratio were upregulated by overloaded mechanical stretch. Pretreatment with inhibitor, rapamycin, could attenuate the activation of and the secretion of in OBs. Interestingly, based on the Trap staining, the supernatant of OBs exposed to OOF could promote osteoclastic differentiation of mesenchymal stem cells (MSCs), while its role was weakened by inhibition of in OBs. Collectively, OOF induced condylar bone absorption; in the process, osteoclastogenesis was prominent than osteogenesis. The activation of and secretion of were enhanced by OOF and were involved in promoting MSCs differentiating into OCs.