The Bone Morphogenetic Proteins and Their Antagonists

The bone morphogenetic proteins (BMPs) and the growth and differentiation factors comprise a single family of some 20 homologous, dimeric cytokines which share the cystine-knot domain typical of the TGF-β superfamily. They control the differentiation and activity of a range of cell types, including many outside bone and cartilage. They serve as developmental morphogens, but are also important in chronic pathologies, including tissue fibrosis and cancer. One mechanism for enabling tight spatiotemporal control of their activities is through a number of antagonist proteins, including Noggin, Follistatin, Chordin, Twisted gastrulation (TSG), and the seven members of the Cerberus and Dan family. These antagonists are secreted proteins that bind selectively to particular BMPs with high affinity, thereby blocking receptor engagement and signaling. Most of these antagonists also possess a TGF-β cystine-knot domain. Here, we discuss current knowledge and understanding of the structures and activities of the BMPs and their antagonists, with a particular focus on the latter proteins. Recent advances in structural biology of BMP antagonists have begun the process of elucidating the molecular basis of their activity, displaying a surprising variety between the modes of action of these closely related proteins. We also discuss the interactions of the antagonists with the glycosaminoglycan heparan sulfate, which is found ubiquitously on cell surfaces and in the extracellular matrix.