Bone morphogenetic proteins (BMPs) are a group of secreted signaling molecules as cytokines and they are the members of the TGF-beta superfamily. BMPs are named for the function of regulating cartilage and bone formation. BMPs exhibit roles in the regulation of bone induction, maintenance, and repair. They are important determinants of mammalian embryological development and induce osteoblast differentiation of various types of cells including undifferentiated mesenchymal cells, bone marrow stromal cells, and preosteoblasts. BMP-2 and BMP-4 have been established to be the key factors in embryonic skeletal development. BMP receptors are the transmembrane receptors classified as type I or type II based on sequence homology and they both contain a C-terminal Serine/Threonine protein kinase.
More than 20 structurally and functionally related members are in BMP subfamily. Active BMPs are usually homodimers with a characteristic cysteine knot structure which is one character of TGF beta family. For instance, BMP-2/BMP-7 homodimer and BMP-4/BMP-7 homodimer have been demonstrated to exist and also function in vivo. Homodimers of BMPs are more potent than respective homodimers as inducers of bone formation. Otherwise, heterodimers are inducers of ventral mesoderm. BMP proteins play key roles in embryogenesis and morphogenesis.
BMP signal in physiology is emphasized by roles of dysregulated BMP signaling in pathological processes. For example, cancers are often related to the absence of the BMP signaling. However, overactivation of BMP signaling induces esophagitis provokes Barrett's esophagus and adenocarcinoma in gastrointestinal tract.
BMP ligand binding to type I receptor (BMPRI/ActRI) induces the association of BMPRI and BMPRII receptors, allowing the constitutively phosphorylated BMPRII to phosphorylate and activate the latent BMPRI. After activation of BMPRI, R-Smad is phosphorylated. Phosphorylation of R-Smad releases itself from the receptor complex and forms heterocomplex by associating with Smad4. Subsequently, the R-Smad/CoSmad complex translocates into the nucleus and regulates the transcription of target genes by functioning in concert with other transcription factors. Signal transduction through BMPRs leads mobilization of SMAD family members. So, the signaling pathways include BMPs, BMPRs and SMADs. These pathways are important in the development of organs such as central nervous system, heart, and cartilage and post-natal bone. Recombinant human BMPs have been applied in orthopedic fields such as spinal fusions, nonunions and oral surgery.
The structural analyses revealed that the surfaces of BMPs have two prominent hydrophobic patches, the convex type II receptor-binding interface (knuckle epitope) and the concave type I receptor-binding interface (wrist epitope).