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

Abstract

The transcription factor Runx2 and the Wnt/β-catenin pathway are major regulators of bone formation. Our aim was to assess the interactions between the Wnt/β-catenin pathway and Runx2 that contribute to bone resorption. Our results indicate that the activity of the canonical Wnt/β-catenin pathway depends on Runx2. Runx2 overexpression inhibited β-catenin levels and activity invitro and invivo. Inhibition of Gsk3b using lithium chloride in Runx2-overexpressing osteoporotic female mice rescued the Wnt/β-catenin signaling invivo and completely restored trabecular bone volume by increasing bone formation and decreasing bone resorption. The activation of Wnt/β-catenin signaling by lithium chloride treatment reduced the number and activity of bone marrow-derived osteoclast-like cells invitro, suggesting that the restoration of trabecular bone invivo was due to decreased bone resorption, consistent with the reduced receptor activator of NF-κB ligand/osteoprotegerin ratio in Runx2-overexpressing osteoblasts. Lithium chloride also increased osteoblast differentiation and activity invitro in agreement with the increase in mineral apposition rate and osteocalcin expression detected invivo. Our results indicate that the activity of the canonical Wnt/β-catenin pathway in osteoblast is modulated by Runx2. To conclude, our invivo and invitro results highlight the role of Runx2 as a negative regulator of Wnt/β-catenin pathway activity in osteoblasts and indicate that theabnormal Wnt/β-catenin activity seen in Runx2 transgenic mice affects both osteoblast and osteoclast differentiation and activity.