Biology of bone morphogenetic proteins

Abstract

Morphogens are signaling molecules that provide positional information to developing tissues and control conformation and histologic architecture of tissues by regulating specific gene expression. The morphogenic feature of BMPs was first described by Marshall Urist in 1965, when he discovered that demineralized bone matrix induced bone formation at extraskeletal sites [1] (see the chapter by Rueger). Since then, the molecules responsible for this phenomenon were isolated, cloned and identified as members of the TGF-β superfamily [2–9]. These signaling molecules were identified in many species, suggesting that they evolved from a group of ancestral genes with their functions refined to meet the needs of particular species. Among17 proteinsso far identified as BMPs, eight have been found to be involved in regulating bone formation and repair. The process of ectopic bone formation is similar to the endochondral bone formation seen during embryonic skeletal development, and the capability of forming new bone is shared by no other growth factor. BMPs are pleiotropic regulators that act at all the important steps in the cascade of events that form new bone: chemotaxis of progenitor cells, mitosis, differentiation and proliferation of chondrocytes and osteoblasts [9, 10]. BMPs also stimulate extracellular matrix formation [9, 11–16] and bind to specific matrix molecules [8, 17–19, 20–22] affecting bone remodeling. Many studies on the cellular activities of BMPs indicate that, as expected from their activities in animal systems, they essentially act as differentiation factors, causing induction and increased expression of multiple differentiated phenotypes in mesenchymal cells [23–30].