5 The Bone Morphogenetic Proteins

Bone morphogenetic proteins (BMPs) have critical roles in skeletal development by regulating the proliferation, differentiation, and apoptosis of many types of cells. Molecular cloning of BMPs and identification of molecules homologous to them have shed light on the novel functions of BMPs in vertebrates as well as in invertebrates, including Drosophila and nematodes. In this chapter, we describe biochemical properties and biological activities of BMPs; we focus, in particular, on the cell differentiation induced by BMPs. Although BMPs are now known to be multifunctional factors in vertebrates and invertebrates, they were originally discovered and identified as a bone-inducing activity in bone matrix in 1965. Marshall R. Urist (1965) first prepared demineralized bone by treating bone with hydrochloric acid and then implanting the demineralized bone in muscular tissues. A few weeks after transplantation, he found that new cartilage and bone tissues with bone marrow had been ectopically formed in muscular tissue (Urist 1965). These findings clearly indicated that the demineralized bone matrix contained unknown bioactive substance(s) capable of inducing differentiation of bone-forming cells in muscular tissues. This ectopic bone-inducing activity was subsequently named “bone morphogenetic protein,” because it disappeared after trypsin digestion (Urist and Strates 1971). However, all attempts to isolate and identify BMP were unsuccessful for more than 20 years after Urist’s original findings because of the difficulty in isolating BMP from bone matrix. BMP activity was water insoluble and could be extracted from demineralized bone matrix with protein denaturants (Urist and Strates 1971; Sampath and Reddi 1981; Yoshikawa et...