8 Role of Growth Factors in Bone Development and Differentiation

Bone is a form of highly specialized mineralized connective tissue that provides strength to the skeletal system of higher vertebrates, while still retaining a certain degree of elasticity. The bone matrix is produced by osteoblasts, a cell-type that develops locally from mesenchymal precursors, and is resorbed by the osteoclast, a cell-type of hematopoietic origin. A few elements, such as the flat bones of the skull and part of the clavicle, are formed by the process of intramembranous ossification, whereby osteoblasts differentiate directly from cells within mesenchymal condensations. In contrast, the majority of skeletal elements are formed by endochondral ossification involving the remodeling of initial cartilaginous templates into bony tissue. The latter process requires controlled maturation of chondrocytes from proliferating and prehypertrophic to hypertrophic chondrocytes, as well as signaling from the prehypertrophic cells to the surrounding cells in the perichondrium, resulting in a regional induction of osteoblast differentiation. Osteoblasts start to differentiate in the periosteum, a region flanking prehypertrophic and hypertrophic chondrocytes. The typical appearance of one end of a juvenile long bone still containing a cartilaginous growth plate is shown in Figure 1. Recent lineage studies suggest that osteoblasts and chondrocytes share a common precursor in the limb. Thus, especially in the limb, the activation and/or inhibition of distinct signaling pathways is necessary in order to coordinate the differentiation of neighboring cells into distinct cell lineages and to synchronize their maturation. This chapter focuses on genetic and molecular studies elucidating the role of different locally produced growth factors during embryonic...