Cellular interactions and signaling in cartilage development

Abstract

The long bones of the developing skeleton, such as those of the limb, arise from the process of endochondral ossification, where cartilage serves as the initial anlage element and is later replaced by bone. One of the earliest events of embryonic limb development is cellular condensation, whereby pre-cartilage mesenchymal cells aggregate as a result of specific cell-cell interactions, a requisite step in the chondrogenic pathway. In this review an extensive examination of historical and recent literature pertaining to limb development and mesenchymal condensation has been undertaken. Topics reviewed include limb initiation and axial induction, mesenchymal condensation and its regulation by various adhesion molecules, and regulation of chondrocyte differentiation and limb patterning. The complexity of limb development is exemplified by the involvement of multiple growth factors and morphogens such as Wnts, transforming growth factor-beta and fibroblast growth factors, as well as condensation events mediated by both cell-cell (neural cadherin and neural cell adhesion molecule) and cell-matrix adhesion (fibronectin, proteoglycans and collagens), as well as numerous intracellular signaling pathways transduced by integrins, mitogen activated protein kinases, protein kinase C, lipid metabolites and cyclic adenosine monophosphate. Furthermore, information pertaining to limb patterning and the functional importance of Hox genes and various other signaling molecules such as radical fringe, engrailed, Sox-9, and the Hedgehog family is reviewed. The exquisite three-dimensional structure of the vertebrate limb represents the culmination of these highly orchestrated and strictly regulated events. Understanding the development of cartilage should provide insights into mechanisms underlying the biology of both normal and pathologic (e.g. osteoarthritis) adult cartilage.