22 TGF-β Family Signaling in Skeletal Development, Maintenance, and Disease

The transforming growth factor-β (TGF-β) family is critically involved in the development and maintenance of skeletal tissues. In searches for factors with potent cartilage and bone inductive activities, TGF-β was isolated as cartilage-inducing factor (Seyedin et al. 1987), whereas bone morphogenetic proteins (BMPs) were isolated as factors able to induce cartilage and bone formation (Urist 1965; Luyten et al. 1989). The TGF-β family shows extensive redundancy of ligands, receptors, agonists, and antagonists, yet the diverse temporal and spatial patterns of expression of each pathway component allow these signaling factors to direct skeletal development and homeostasis by regulating patterning, cell-fate determination, cell differentiaton, and bone remodeling. The critical roles of each factor are evident in mice with mutations in components of these pathways, whereas in vitro studies have elucidated the mechanisms for the action of the TGF-β family in mesenchymal and skeletal cells. Because the TGF-β family has a central role in the regulation of mesenchymal differentiation into skeletal cells, its role in osteoblast and chondrocyte development is detailed in Chapter 21. Here we discuss, at the tissue level, the impact of TGF-β family ligands and signaling pathways in skeletal patterning, skeletal development, and skeletal maintenance and metabolism, as well as the effects of their deregulation in many skeletal diseases. IMPLICATION AND LOCALIZATION OF TGF-β FAMILY SIGNALING COMPONENTS IN THE SKELETON Many members of the TGF-β family, their receptors, and signaling effectors, the Smads, are widely expressed in mesenchymal tissues throughout development and, in particular, at sites of skeletal patterning and...