Secreted BMP antagonists and their role in cancer and bone metastases

Bone morphogenetic proteins (BMPs) are multifunctional secreted cytokines that act in a highly context-dependent manner. BMP action extends beyond the induction of cartilage and bone formation, to encompass pivotal roles in controlling tissue and organ homeostasis during development and adulthood. BMPs signal via plasma membrane type I and type II serine/threonine kinase receptors and intracellular SMAD transcriptional effectors. Exquisite temporospatial control of BMP/SMAD signalling and crosstalk with other cellular cues is achieved by a series of positive and negative regulators at each step in the BMP/SMAD pathway. The interaction of BMP ligand with its receptors is carefully controlled by a diverse set of secreted antagonists that bind BMPs and block their interaction with their cognate BMP receptors. Perturbations in this BMP/BMP antagonist balance are implicated in a range of developmental disorders and diseases, including cancer. Here, we provide an overview of the structure and function of secreted BMP antagonists, and summarize recent novel insights into their role in cancer progression and bone metastasis. Gremlin1 (GREM1) is a highly studied BMP antagonist, and we will focus on this molecule in particular and its role in cancer. The therapeutic potential of pharmacological inhibitors for secreted BMP antagonists for cancer and other human diseases will also be discussed.