Acceleration of bone regeneration by local application of lithium: Wnt signal-mediated osteoblastogenesis and Wnt signal-independent suppression of osteoclastogenesis

Inhibition of glycogen synthase kinase (GSK)-3 and the consequent activation of the Wnt/beta-catenin signaling pathway have been reported to increase bone volume. To develop a novel pharmacotherapy for injured bone, we investigated whether GSK-3 inhibitor was effective in promoting bone formation. In in vitro experiments, we examined the effects of GSK-3 inhibitors LiCl and SB216763 on osteoblastogenesis of mesenchymal progenitor C3H10T1/2 cells and osteoclastogenesis of osteoclast precursor RAW-D cells. Both inhibitors promoted osteoblast differentiation, assessed by alkaline phosphatase activity and calcium deposition, stimulating the Wnt/beta-catenin signaling pathway and thereby inducing Runx2. On the other hand, the GSK-3 inhibitors suppressed osteoclast differentiation, assessed by tartrate-resistant acid phosphatase staining and number of nuclei in the cells, reducing NFATc1 expression independently of the Wnt/beta-catenin signaling pathway. In subsequently performed in vivo studies, we examined the effect of locally administered Li2CO3 on the recovery from a partial defect made on the rat tibia. Computerized tomography and bone histomorphometry showed that Li2CO3 accelerated bone regeneration in defect lesion with increased lamellar bone ratio compared with the controls. These results suggested that local application of lithium (or other GSK-3 inhibitors) might effectively facilitate recovery from bone injury by promoting osteoblastogenesis and inhibiting osteoclastogenesis. (C) 2014 Elsevier Inc. All rights reserved.