Bone morphogenetic proteins and their antagonists: current and emerging clinical uses

Abstract

Bone morphogenetic proteins (BMPs) are members of the TGFβ superfamily of secreted cysteine knot proteins that includes TGFβ1, nodal, activins and inhibins. BMPs were first discovered by Urist in the 1960s when he showed that implantation of demineralized bone into intramuscular tissue of rabbits induced bone and cartilage formation. Since this seminal discovery, BMPs have also been shown to play key roles in several other biological processes, including limb, kidney, skin, hair and neuronal development, as well as maintaining vascular homeostasis. The multifunctional effects of BMPs make them attractive targets for the treatment of several pathologies, including bone disorders, kidney and lung fibrosis, and cancer. This review will summarize current knowledge on the BMP signalling pathway and critically evaluate the potential of recombinant BMPs as pharmacological agents for the treatment of bone repair and tissue fibrosis in patients.

Keywords: bone morphogenetic protein; fibrosis; fracture; gremlin; inhibitors; scarring; skeleton.

Figure 1

Model of BMP synthesis and site-specific cleavage by proprotein convertases. BMPs are synthesized within the cell as large, inactive dimeric precursor proteins within the ER that require site-specific cleavage by proprotein convertases to produce stable, active dimers. This occurs at two sites located within its pro-domain. Initial cleavage at S1 site is thought to occur in the TGN and results in a pro-domain–ligand complex. This pro-domain–ligand complex is further cleaved at S2 site, which is rendered accessible due to the acidic enviroment within the post-TGN. This releases the mature ligand from the pro-domain, yielding a stable biologically active BMP monomer. ER, endoplasmic reticulum; TGN, trans-Golgi network; CM, cell membrane.

Figure 2

Activation and regulation of BMP/Smad-dependent signalling. BMP ligands bind to and activate type I and II serine/threonine kinase receptors (BMPR-I and BMPR-II, respectively), which triggers phosphorylation of the R-Smad1/5/8. Phosphorylated R-Smads form a heteromeric complex with the co-Smad 4, enabling its subsequent translocation to the nucleus where it binds to specific GC rich sequences within the promoters of several target genes in concert with various DNA binding co-factors. This cascade is tightly regulated, through pseudo-receptors such as BAMBI, which quench BMP ligands thereby limiting their availability to interact with their receptors. Extracellular regulation occurs via direct interaction of BMPs with their secreted antagonists, thereby preventing ligand receptor interaction. Intracellularly, this pathway is regulated by the I-Smads, Smad6 and 7. Smad6 prevents the formation of R-Smad and co-Smad complex formation. Smad7 regulates this pathway by forming a complex with Smurf1/2 and competing with R-Smad for type I receptor-mediated activation effectively antagonizing BMP/Smad pathway activation. This pathway is also regulated by phosphatases such as PP1, which dephosphorylates the BMP type I receptor, and PPM1A, which dephosphorylates R-Smads. R-Smad, receptor regulated Smads; I-Smad, inhibitory Smads; co-Smad, co-mediator Smad; ID, inhibitor of differentiation; PAI1, plasminogen activator inhibitor-1; PP1, protein phosphatase 1; PPM1A, metal ion-dependent protein phosphatases 1A; DBC, DNA binding co-factors; PM, plasma membrane.