Pharmaceutical inhibition of glycogen synthetase kinase 3 beta suppresses wear debris-induced osteolysis.
Aseptic loosening is associated with the development of wear debris-induced peri-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 peri-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-3β), mitigates wear debris-induced osteolysis in a murine calvarial model of osteolysis. GSK-3β 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-3β activity and increased β-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-3β 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-3β and, therefore, the canonical Wnt signaling pathway. This suggests that selective inhibitors of GSK-3β such as LiCl may help prevent and treat wear debris-induced osteolysis.
Department of Orthopedics, The First Affiliated Hospital of Soochow University, People's Republic of China. Electronic address: szgengdc@163.com.
Dechun
D
Geng
Department of Rheumatology, The First Affiliated Hospital of Soochow University, People's Republic of China.
Jian
J
Wu
Department of Orthopedics, The First Affiliated Hospital of Soochow University, People's Republic of China.
Hongguo
H
Shao
Department of Orthopedics, The First Affiliated Hospital of Soochow University, People's Republic of China.
Shijun
S
Zhu
Department of Orthopedics, The First Affiliated Hospital of Soochow University, People's Republic of China.
Yijun
Y
Wang
Orthopedic Institute, Soochow University, People's Republic of China.
Wen
W
Zhang
Department of Orthopedics, The First Affiliated Hospital of Soochow University, People's Republic of China.
Zichuan
Z
Ping
Department of Orthopedics, The First Affiliated Hospital of Soochow University, People's Republic of China.
Xuanyang
X
Hu
Department of Orthopedics, The First Affiliated Hospital of Soochow University, People's Republic of China.
Xuesong
X
Zhu
Department of Orthopedics, The First Affiliated Hospital of Soochow University, People's Republic of China. Electronic address: xuyaozeng@163.com.
Yaozeng
Y
Xu
Department of Orthopedics, The First Affiliated Hospital of Soochow University, People's Republic of China. Electronic address: yhlsuzhou@126.com.
Huilin
H
Yang
D000818:Animals; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018021:Lithium Chloride / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D010014:Osteolysis / Q000188:drug therapy* / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D019736:Prostheses and Implants / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012886:Skull / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D014025:Titanium / Q000009:adverse effects
D047428:Protein Kinase Inhibitors; D014025:Titanium; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride
Lithium chloride; Osteoblast; Osteoclast; Osteolysis; Wear debris