Microenvironmental and structural regulation of BMP signaling: insights into the prodomain-growth factor interface

Bone morphogenetic proteins (BMPs) are extracellular, pluripotent cytokines that regulate diverse cellular processes. Despite their critical roles, the mechanisms controlling their bioavailability within the extracellular microenvironment remain poorly understood. This review highlights recent advances in BMP regulation at the prodomain-growth factor interface, focusing on intra- and extracellular mechanisms that govern BMP activation. By modulating receptor accessibility, this interface serves as a key determinant of BMP activity. Major regulatory processes include propeptide convertase processing, interactions with glycosaminoglycans, incorporation into supramolecular extracellular matrix scaffolds, and activation through proteolytic cleavage of BMP prodomains. A deeper understanding of these mechanisms provides new therapeutic insights into conditions associated with dysregulated BMP signaling, including cardiovascular disease and cancer.