Bone Morphogenetic Protein-Based Therapeutic Approaches

Abstract

Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor (TGF)-β family of ligands and exert most of their effects through the canonical effectors Smad1, 5, and 8. Appropriate regulation of BMP signaling is critical for the development and homeostasis of numerous human organ systems. Aberrations in BMP pathways or their regulation are increasingly associated with diverse human pathologies, and there is an urgent and growing need to develop effective approaches to modulate BMP signaling in the clinic. In this review, we provide a wide perspective on diseases and/or conditions associated with dysregulated BMP signal transduction, outline the current strategies available to modulate BMP pathways, highlight emerging second-generation technologies, and postulate prospective avenues for future investigation.

Figure 1.

The bone morphogenetic protein (BMP) pathway and potential strategies for therapeutic modulation. (1) Activation of the BMP pathway occurs via interaction between dimeric BMP ligands and complexes of type I (e.g., ALK-2 and ALK-3) and type II receptors (BMPRII, ActRII, or ActRIIB). This step may be inhibited by delivery of extracellular ligand traps such as naturally occurring antagonists, receptor decoys, or neutralizing antibodies. Alternatively, BMP ligand availability may be enhanced through delivery of exogenous ligands or inhibiting endogenous extracellular BMP antagonists by neutralizing antibodies or small molecules. (2) Ligand binding leads to activation of the type I receptors by type II receptors and subsequent phosphorylation of the receptor-activated Smads 1, 5, and 8 (R-Smads) along with other pathways including extracellular signal-regulated kinase (Erk) and p38 mitogen-activated protein kinase (MAPK), and PI3K-Akt. The kinase activities of the type I receptors may be blocked by small molecule inhibitors such as LDN-193189. The BMP pathway inhibitors FKBP12 and casein kinase 2 endogenously limit the activities of the type I receptors and may be inactivated by delivery of FK506 and CK2.3, respectively, to increase BMP signal transduction. (3) R-Smads may perform Smad4-independent activities such as regulating microRNA processing or associate with Smad4 or other transcription factors to control gene regulatory networks. Persistence of BMP signaling may be modulated by regulating the Smurf1-mediated ubiquitylation of Smad effector proteins by disrupting Smurf1 interaction with R-Smads by small molecule inhibitors or by increasing Smurf1 protein levels. (4) R-Smad-dependent and R-Smad-independent events are integrated in a context-dependent manner to control cellular activity.