Canonical Wnt signaling in osteoblasts is required for osteoclast differentiation.

Inactivation of Lrp5, a gene encoding a likely Wnt co-receptor, results in low bone mass (osteopenia) by decreasing bone formation, suggesting that Wnt signaling in osteoblasts regulates bone formation. Here we show that Tcf1 and Tcf4 are expressed in osteoblasts during development and after birth; stabilization of beta-catenin, an essential component of canonical Wnt signaling, in differentiated osteoblasts results in high bone mass while its deletion from differentiated osteoblasts leads to osteopenia. Histological analysis showed that these mutations affect bone resorption. Cellular and molecular studies showed that beta-catenin together with TCF proteins regulates in osteoblasts the expression of Osteoprotegerin, a major inhibitor of osteoclast differentiation. These findings demonstrate that, in differentiated osteoblasts, beta-catenin and presumably Wnt signaling are negative regulators of osteoclast differentiation; thus they broaden our knowledge about functions that Wnt proteins may have at various stages of skeletogenesis.