Pharmaceutical inhibition of glycogen synthetase kinase 3 beta suppresses wear debris-induced osteolysis

Aseptic loosening is associated with the development of wear debris-induced pen-implant osteolytic bone disease caused by an increased osteoclastic bone resorption and decreased osteoblastic bone formation. However, no effective measures for the prevention and treatment of pen-implant osteolysis currently exist. The aim of this study was to determine whether lithium chloride (LiCl), a selective inhibitor of glycogen synthetase kinase 3 beta (GSK-3 beta), mitigates wear debris-induced osteolysis in a murine calvarial model of osteolysis. GSK-3 beta is activated by titanium (Ti) particles, and implantation of Ti particles on the calvarial surface in C57BL/6 mice resulted in osteolysis caused by an increase in the number of osteoclasts and a decrease in the number of osteoblasts. Mice implanted with Ti particles were gavage-fed LiCl (50 or 200 mg kg(-1)d(-1)), 6 days per week for 2 weeks. The LiCl treatment significantly inhibited GSK-3 beta activity and increased beta-catenin and axin-2 expression in a dose-dependent manner, dramatically mitigating the Ti particle-induced suppression of osteoblast numbers and the expression of bone formation markers. Finally, we demonstrated that inhibition of GSK-3 beta suppresses osteoclast differentiation and reduces the severity of Ti particle-induced osteolysis. The results of this study indicate that Ti particle-induced osteolysis is partly dependent on GSK-3 beta and, therefore, the canonical Wnt signaling pathway. This suggests that selective inhibitors of GSK-3 beta such as LiCl may help prevent and treat wear debris-induced osteolysis. (C) 2015 Elsevier Ltd. All rights reserved.