Bone Morphogenetic Proteins (BMPs) are a family of ligands that belong to the Transforming Growth Factor β (TGFβ) superfamily (Wozney, 1989). They were originally recognized for their ability to induce endochondral bone formation (Urist, 1965).
From the time of Hippocrates it has been known that bone has considerable potential for regeneration and repair. Senn, a surgeon at Rush Medical College in Chicago, described the utility of antiseptic decalcified bone implants in the treatment of osteomyelitis and certain bone deformities (Senn, 1889). Pierre Lacroix proposed, that in bone, there might be a hypothetical substance, osteogenin, that might initiate bone growth (Lacroix, 1945).
The biological basis of bone morphogenesis was shown by Marshall R. Urist. Urist made the key discovery that demineralized, lyophilized segments of bone induced new bone formation when implanted in muscle pouches in rabbits. This seminal discovery was published in 1965 by Urist in Science (Urist, 1965). Marshall Urist proposed the name "Bone Morphogenetic Protein" in the scientific literature in the Journal of Dental Research in 1971 (Urist, 1971). Marshall Urist died on February 4, 2001. A tribute to him and his research was written in the Journal of Bone and Joint Surgery (Reddi, 2003).
Bone induction is a sequential multistep cascade. The key steps in this cascade are chemotaxis, mitosis, and differentiation. Early studies by Hari Reddi unraveled the sequence of events involved in bone matrix-induced bone morphogenesis (Reddi, 1972). On the basis of the above work, it seemed likely that morphogens were present in the bone matrix. Using a battery of bioassays for bone formation, a systematic study was undertaken to isolate and purify putative bone morphogenetic proteins.
A major stumbling block to purification was the insolubility of demineralized bone matrix. To overcome this hurdle, A. Hari Reddi and Kuber Sampath used dissociative extractants, such as 4M guanidine HCL, 8M Urea, or 1% SDS (Sampath, 1981). The soluble extract alone or the insoluble residues alone were incapable of new bone induction. This work suggested that the optimal osteogenic activity requires a synergy between soluble extract and the insoluble collagenous substratum. It not only represented a significant advance toward the final purification of bone morphogenetic proteins (BMPs) by the Reddi laboratory (Sampath 1987; Luyten, 1989), but ultimately also enabled the cloning of BMPs by John Wozney and colleagues at Genetics Institute (Wozney, 1989).
Like all members of the TGFβ superfamily, BMPs are expressed as long precursor proteins, carrying an N-terminal signal peptide, a prodomain and the C-terminal mature peptide. The signal peptide directs the protein to the secretory pathway, while the prodomain mediates proper folding (Miyazono, 1988). BMP monomers are stabilized by a structure known as cystine knot motif: six highly conserved cysteines form three intramolecular disulfide bonds. BMPs are typically secreted as homomeric dimers. Stabilization of the dimer is mediated through an additional cysteine bridge, requiring a seventh cysteine within each monomer (Griffitz, 1996; Scheufler, 1999). Some members of the BMP family, e.g. GDF3 (McPherron, 1993), GDF9 (McPherron, 1993), and GDF9B (BMP15; Dube, 1998) lack the seventh cysteine. However, they are biologically active and may form non-covalent dimers (Liao, 2003). Furthermore, several studies report that BMP heterodimers are more potent than their corresponding homodimers (Israel, 1996). The secretion of heterodimers was observed for BMP4/7 (Aono, 1995; Suzuki, 1997; Kusomoto, 1997), BMP2/5 (Ref), BMP2/6 (Ref), BMP2/7 (Ref), BMP15/GDF9 (Israel, 1996), and BMP2b/7 (Little, 2009). Serine endoproteases cleave the proprotein within the trans-Golgi network, producing the mature protein that is subsequently secreted (Cui, 1998). For some BMPs, e.g. BMP7 (OP1; Jones, 1994) and GDF8 (Myostatin; Thies, 2001) the proregion was shown to remain attached to the mature protein even after secretion.
BMPs interact with specific receptors on the cell surface, referred to as bone morphogenetic protein receptors (BMPRs).
Signal transduction through BMPRs results in phosphorylation of downstream targets. The best characterized signaling cascade is the Smad pathway. It was shown to be important in the development of the heart, central nervous system, and cartilage, as well as post-natal bone development.
They have an important role during embryonic development on the embryonic patterning and early skeletal formation. As such, disruption of BMP signaling can affect the body plan of the developing embryo. For example, BMP4 and its antagonists Noggin and Chordin help regulate polarity of the embryo (i.e. back to front patterning).
Mutations in BMPs and their antagonists, for example Sclerostin, are associated with a number of human disorders that affect the skeleton and other tissues.
Several BMPs are also named 'cartilage-derived morphogenetic proteins' (CDMPs), while others are referred to as 'growth differentiation factors' (GDFs).
Medical / Clinical Application