Bone Morphogenetic Protein-7 (BMP-7), also called Osteogenic Protein 1 (OP-1), was originally identified as one of the growth factors involved in the formation of bone.  Subsequent studies revealed the importance of this protein for a range of developments, including kidney patterning, especially during the embryonic stage.  It is some times referred to as a metabologen since it also initiates, promotes, and maintains metabolism, especially with regard to brown fat adipogenesis and energy metabolism.

Subsequent study of the underlying biomolecular processes revealed that BMP-7 modulates an anti-fibrotic pathway in competition with other members of the TGF-β superfamily of growth factors.  While BMP-7 is itself a member of the same superfamily, it interacts with a different surface receptor on the cell.  TGF-β and BMP-7 both interact with RTK (receptor tyrosine kinase)-type transmembrane receptors which, when bound to their ligand, cause phosphorylation of SMAD signaling proteins inside the cell.  The phosphorylated SMAD proteins then complex with SMAD4 as a mediator to create a signaling cascade that culminates with the induction of transcriptional responses in the nucleus.  Depending on which signals reach the nucleus, either BMP-dependent genes or TGF-β-dependent genes undergo transcription.

The signaling cascades activate transcription of different genes.  When BMP-7 is bound to its receptor, it phosphorylates SMAD 1,5, and 8 resulting in transcription of antifibrotic genes, while TGF-β binding to its receptor phosphorylates SMAD 2 and 3 and results in transcription of profibrotic genes.  If the ligands for both BMP-7 and TGF-β are bound to their receptors, the cell will transcribe antifibrotic genes because the limited amount of SMAD4 preferentially complexes with the SMAD proteins associated with the BMP-7 receptor.

Dysregulation of this process leads to deposition of excess cellular matrix, especially in the kidney, where it leads to renal fibrosis and declines in filtration rates.  In animal models BMP-7 has been shown to be renoprotective through a number of mechanisms as shown below.

During the progression of chronic kidney disease, persistent activation of TGF-β and suppression of BMP-7 leads to the erosion of the innate repair mechanisms of the kidneys, renal fibrosis, and end-stage renal disease as shown in the diagram below.¹  There is evidence suggesting that BMP-7 is more strongly expressed during growth phases of life, but that expression is attenuated in early adulthood.  The TGF-β family of cytokines are implicated in nearly every inflammatory and fibrotic disease, and restoration of a balance between BMP-7 and TGF-β is believed to provide benefits in a number of disease states.

In addition to renal disease, BMP-7 has been shown to reduce LOX1-mediated deposition of Type I collagen in liver fibrosis, and the mechanism of action suggests that it will work equally well in other chronic diseases.

A recombinant form of BMP-7 was developed in the early 1990's for use as a bone growth agent, and a major orthopedic company obtained approval for a bone putty product containing a quantity of the protein.  Bone putty is regulated as a medical device, so the protein has never been investigated or approved as a biologic drug for treating fibrotic conditions or other diseases, despite more than 1,000 scientific articles published on the effects of BMP-7 for a wide range of conditions.

1. Manson, S, et al., BMP-7 Signaling and its Critical Roles in Kidney Development, the Responses to Renal Injury, and Chronic Kidney Disease. Vitam Horm 2015 Vol. 99 Pages 91-144.