IBMS BoneKEy | Perspective
Non-canonical Wnt signaling: What is its role in bone?
Joseph Caverzasio
DOI:10.1138/20090368
Abstract
Recent findings indicate that Wnt proteins are important for the acquisition of bone mass. The role of these proteins was inferred from the identification of mutations in the Wnt co-receptor low-density lipoprotein receptor-related protein 5 (Lrp5) in patients with heritable skeletal diseases. Mice with conditional deletion of β-catenin in limb and head mesenchyme during early embryonic development exhibit an arrest of osteoblastic differentiation and a lack of mature osteoblasts in membranous bones, demonstrating the importance of Wnt proteins for the development of osteoprogenitors. However, high β-catenin levels in differentiated osteoblasts increase OPG expression and exert a strong negative effect on osteoclast differentiation. In addition, a recent in vivo analysis of the role of Lrp5 in osteoblasts gave surprising results: ablation of Lrp5 in osteoblasts had no effect on bone formation. Instead, it seems that the effect of global alteration of Lrp5 on bone metabolism is linked to changes in circulating levels of serotonin. Thus, the direct, cell-autonomous effect of Wnt proteins on osteoblasts stands in need of reconsideration. As described in this Perspective, Wnt proteins can activate different types of receptors in osteoblasts and recent studies suggest that non-canonical pathways may play an important role in controlling the development of osteoblast lineage cells and the activity of osteoblasts, suggesting that an understanding of non-canonical signaling in bone cells may lead to new therapeutic strategies for the treatment of osteoporosis.
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