33 BMP-based Therapeutics and the BMP Signaling Pathways

The bone morphogenetic proteins (BMPs) were originally identified as molecules responsible for the bone-inductive activity present within bone matrix (Wozney et al. 1988). Now known to be a family of proteins within the larger transforming growth factor-β (TGF-β) family, the BMPs have a wide range of activities on various cell types (see Chapter 5). As discussed elsewhere in this volume, the BMP signaling system parallels, but is distinct from, that of TGF-β. BMP signaling is tightly controlled by a range of extracellular, intracellular, and nuclear modulators, suggesting many targets for pharmaceutical intervention. In this chapter, we discuss some of the potential therapeutic applications of the BMPs and locations in the BMP pathway that may lend themselves to development of therapeutics. Depending on the biology of the BMP, stimulation of the pathway, for example, by supplying exogenous ligand or by increasing endogenous expression, may provide a therapeutic; alternatively, suppression of the pathway via inhibition may be the desired therapeutic approach. In the latter part of the chapter, we give two examples of development of pharmaceuticals. In one case, the therapeutic is the BMP ligand itself; in the other, an inhibitor of the ligand is being evaluated. POTENTIAL THERAPEUTIC APPLICATIONS OF THE BMPS The BMPs are a family of growth and differentiation factors, some of which are expressed in almost every cell type. They have autocrine, paracrine, and perhaps even endocrine functions. Most are believed to be locally acting factors, but some circulate and have been reported to have systemic activities. The...