Cellular signaling in developmental chondrogenesis: N-cadherin, Wnts, and BMP-2.

Abstract

Cartilage formation in the developing vertebrate embryonic limb consists of a highly coordinated and orchestrated series of events involving the commitment, condensation, and chondrogenic differentiation of mesenchymal cells and the production of the cartilaginous matrix 1. Endochondral ossification ensues upon maturation and hypertrophy of the cartilage, resulting in the formation of the osseous elements of the limb. The recapitulation of this sequence of events during skeletal wound-healing and fracture-healing in postnatal life underscores the importance of understanding the cellular and molecular mechanisms that are responsible for initiating and regulating the early steps of cartilage development. Embryonic cartilage development has been shown to be under the regulation of a number of biological factors, including members of the transforming growth factor-β (TGF-β) superfamily such as the bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), and the Wnt family of secreted glycoproteins as well as cell adhesion proteins (e.g., neural cadherin [N-cadherin] and neural cell adhesion molecule [N-CAM]) and extracellular matrix (ECM) molecules (e.g., fibronectin, proteoglycans, and various collagen types)1. This paper briefly reviews our recent studies on the mechanisms responsible for mesenchymal condensation and chondrogenic differentiation, and the role of Wnt members, as related to N-cadherin-mediated functions and the action of BMP-2, in the regulation of these processes. The Wnts are a large family of cysteine-rich glycoproteins that have been shown to perform a wide variety of inductive and regulatory functions in both normal development and oncogenic transformations1-3. The expression of various Wnts has been identified in the developing limb bud 4,5, and it has been shown that some Wnts may act in a chondro-inhibitory fashion when introduced during limb development 6-8. Our recent studies have shown that the dual consequences of Wnt signaling on cadherin-mediated cell adhesion and/or gene expression through β-catenin provide at …