Runx2 Controls Bone Resorption through the Down-Regulation of the Wnt Pathway in Osteoblasts

The transcription factor Runx2and the Wnt/β- cateninpathway are major regulators of bone formation. Our aim was to assess the interactions between the Wnt/β- cateninpathway and Runx2that contribute to bone resorption. Our results indicate that the activity of the canonical Wnt/β- cateninpathway depends on Runx2. Runx2overexpression inhibited β- cateninlevels and activity in vitro and in vivo. Inhibition of Gsk3busing lithium chloridein Runx2-overexpressing osteoporotic female mice rescued the Wnt/β- cateninsignaling in vivoand completely restored trabecular bone volume by increasing bone formation and decreasing bone resorption. The activation of Wnt/β- cateninsignaling by lithium chloridetreatment reduced the number and activity of bone marrow–derived osteoclast-like cells in vitro , suggesting that the restoration of trabecular bone in vivowas due to decreased bone resorption, consistent with the reduced receptor activator of NF-κB ligand/ osteoprotegerinratio in Runx2-overexpressing osteoblasts. Lithium chloridealso increased osteoblastdifferentiation and activity in vitro in agreement with the increase in mineral appositionrate and osteocalcin expression detected in vivo. Our results indicate that the activity of the canonical Wnt/β- cateninpathway in osteoblastis modulated by Runx2. To conclude, our in vivoand in vitro results highlight the role of Runx2as a negative regulator of Wnt/β- cateninpathway activity in osteoblastsand indicate that the abnormal Wnt/β- cateninactivity seen in Runx2transgenic mice affects both osteoblastand osteoclast differentiation and activity.