Bone morphogenetic proteins (BMPs) are important signalling molecules that were first identified by their ability to induce bone and cartilage, and subsequently were shown to be pleiotropic cytokines controlling a wide variety of biological responses during early development, skeletogenesis and homoeostasis of several tissues. In agreement with their crucial role in many biological processes, mutations in components of the BMP signalling pathway underlie several pathologies. BMPs transmit their signals from membrane to nucleus through distinct combinations of types I and II serine/threonine kinase receptors and their intracellular effectors the Smad proteins. Smad‐mediated transcription of target genes is regulated in a complex manner in which interactions with other transcription factors and signalling pathways define the final response.
Key Concepts
Bone morphogenetic proteins (BMPs) are important pleiotropic cytokines controlling a wide variety of biological responses ranging from early development, skeletogenesis and homeostasis of several tissues to suppression of tumorigenesis.
In agreement with their crucial role in many biological processes, mutations in components of the BMP signalling pathway underlie several pathologies, including primary pulmonary hypertension and fibrodysplasia ossificans progressiva.
BMPs transmit their signals from membrane to nucleus through distinct combinations of types I and II serine/threonine kinase receptors and their intracellular Smad effector proteins.
An essential step in most BMP receptor‐controlled responses is the phosphorylation of the receptor‐regulated Smads, Smad1, Smad5 and Smad8, which then associate with the co‐Smad, Smad4, and translocate to the nucleus where they control transcription of BMP target genes.
Besides the well‐established BMP/Smad pathway, BMPs can also activate alternative signalling routes, so‐called non‐Smad pathways, which in concert with the Smad pathway determine the BMP‐induced effects.
The pleiotropic characteristics of BMPs clearly implicate the need for a tight control of their activities, which is achieved via secreted antagonists which directly bind BMPs and prevent them from binding to their receptors, negative feedback loops mediated by the inhibitory Smads, Smad6 and Smad7, and crosstalk with many different signalling pathways.
Differential binding of BMP family members to receptors and extracellular antagonists, their ability to activate certain Smad‐independent signalling pathways, differences in signalling amplitude and duration of both Smad‐dependent and Smad‐independent pathways, and how these interact, define the final outcome of BMP‐induced cellular responses.