The Journal of Bone and Joint Surgery (American). 2008;90:19-24.
doi:10.2106/JBJS.G.01174
© 2008 The Journal of Bone and Joint Surgery, Inc.
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Wnt and Hedgehog Signaling Pathways in Bone Development

Timothy F. Day, BS and Yingzi Yang, PhD

Corresponding author:
Yingzi Yang, PhD
Genetic Disease Research Branch, National Human Genome Research Institute, Building 49, Room 4A68, 49 Convent Drive, MSC 4472, Bethesda, MD 20892.
E-mail address: yingzi{at}mail.nih.gov

Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

Cell-cell signaling is a major strategy that vertebrate embryos employ to coordinately control cell proliferation, differentiation, and survival in many developmental processes. Similar cell signaling pathways also control adult tissue regeneration and repair. We demonstrated in the developing skeletal system that the Wnt/β-catenin signaling controls the differentiation of progenitor cells into either osteoblasts or chondrocytes. Genetic ablation of β-catenin in the developing mouse embryo resulted in ectopic formation of chondrocytes at the expense of osteoblast differentiation during both intramembranous and endochondral ossification. Conversely, ectopic upregulation of the canonical Wnt signaling led to suppression of chondrocyte formation and enhanced ossification. As other signaling pathways also play critical roles in controlling skeletal development, to gain a full picture of the molecular regulatory network of skeletal development, we investigated how the Wnt/β-catenin signaling is integrated with Indian hedgehog (Ihh) signaling in controlling various aspects of skeletal development. We found that Wnt signaling acts downstream of Ihh signaling and is required in osteoblasts after Osterix expression to promote osteoblast maturation during endochondral bone formation. Since similar controlling mechanisms of osteoblast proliferation and differentiation may be employed by adult mesenchymal progenitor cells during fracture repair, these studies suggest that, to enhance fracture repair or bone formation, Ihh signaling needs to be enhanced at early stages, whereas Wnt signaling should be upregulated slightly later in differentiated osteoblasts.


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