Bone Morphogenetic Proteins

Abstract

Bone morphogenetic proteins (BMPs), originally identified as osteoinductive components in extracts derived from bone, are now known to play important roles in a wide array of processes during formation and maintenance of various organs including bone, cartilage, muscle, kidney, and blood vessels. BMPs and the related "growth and differentiation factors" (GDFs) are members of the transforming growth factor β (TGF-β) family, and transduce their signals through type I and type II serine-threonine kinase receptors and their intracellular downstream effectors, including Smad proteins. Furthermore, BMP signals are finely tuned by various agonists and antagonists. Because deregulation of the BMP activity at multiple steps in signal transduction is linked to a wide variety of human diseases, therapeutic use of activators and inhibitors of BMP signaling will provide potential avenues for the treatment of the human disorders that are caused by hypo- and hyperactivation of BMP signals, respectively.

Figure 1.

Relationships between bone morphogenetic protein/growth and differentiation factor (BMP/GDF) ligands, type II receptors, type I receptors, and Smad proteins in signal transduction. BMP-1 is a metalloproteinase and is not a member of the transforming growth factor β (TGF-β) family. Structurally related ligands, receptors, and Smad proteins are grouped and shown in the same boxes.

Figure 2.

Potentiators and inhibitors of bone morphogenetic protein (BMP) signaling. Potentiators (left) and inhibitors (right) of BMP signaling are listed. These factors act on signaling extracellularly, at the membrane, in the cytoplasm, or in the nucleus.

Figure 3.

Roles of bone morphogenetic protein (BMP) signaling in skeletal development. Most skeletal elements are formed by endochondral ossification, in which undifferentiated mesenchymal cells condense in response to a GDF-5 signal (top). The cells differentiate into chondrocytes and form cartilaginous tissues. GDF-5 and GDF-6 promote cartilage development through BMPRIB, but noggin suppresses this process as a BMP antagonist to lead a joint formation (middle). The proliferating chondrocytes further differentiate into hypertrophic chondrocytes, and then the terminally differentiated chondrocytes are replaced by bone tissue (bottom). Chondrocyte differentiation is stimulated by BMP-2, BMP-6, and BMP-7 secreted by the chondrocytes themselves, and bone formation is suppressed by BMP-3 secreted by osteocytes.

Figure 4.

Bone morphogenetic proteins (BMPs) are secreted key regulators of an epithelial–mesenchymal interaction in tooth development. Teeth are formed by an epithelial–mesenchymal interaction during tooth development. At an initiation stage, BMP-4 from epithelial cells initiates tooth development through Msx1, a homeobox-containing transcription factor, in mesenchymal cells (top). BMP-2 and BMP-4 from mesenchymal cells act as a positive signal on BMPRIA in initiation of differentiation of epithelial cells at a bud stage (middle). At the bell and cap stages, BMP from epithelial cells regulates odontoblast differentiation in mesenchyme (bottom). BMP signaling is inhibited by BMP antagonists, including noggin, USAG-1, chordin, Gremlin, and follistatin.

Figure 5.

Roles of bone morphogenetic proteins (BMPs) in cancer. Pro- (red) and antitumorigenic (blue) effects of BMPs on various components of cancer microenvironments are shown. BMPs can either promote or suppress the proliferation and progression of cancer cells depending on the cellular contexts. EMT, Epithelial–mesenchymal transition.