Circulating bone morphogenetic protein 1-3 isoform increases renal fibrosis.

Abstract

Bone morphogenetic proteins (BMPs) participate in organ regeneration through autocrine and paracrine actions, but the existence and effects of these proteins in the systemic circulation is unknown. Using liquid chromatography-mass spectrometry, we identified BMP6, GDF15, and the BMP1-3 isoform of the Bmp1 gene in plasma samples from healthy volunteers and patients with CKD. We isolated the endogenous BMP1-3 protein and demonstrated that it circulates as an active enzyme, evidenced by its ability to cleave dentin matrix protein-1 in vitro. In rats with CKD, administration of recombinant BMP1-3 increased renal fibrosis and reduced survival. In contrast, administration of a BMP1-3-neutralizing antibody reduced renal fibrosis, preserved renal function, and increased survival. In addition, treating with the neutralizing antibody was associated with low plasma levels of TGFβ1 and connective tissue growth factor. In HEK293 cells and remnant kidneys, BMP1-3 increased the transcription of collagen type I, TGFβ1, β-catenin, and BMP7 via a BMP- and Wnt-independent mechanism that involved signaling through an integrin β1 subunit. The profibrotic effect of BMP1-3 may, in part, be a result of the accompanied decrease in decorin (DCN) expression. Taken together, inhibition of circulating BMP1-3 reduces renal fibrosis, suggesting that this pathway may be a therapeutic target for CKD.

• Authors: Lovorka Grgurevic, Boris Macek, David R Healy, Amy L Brault, Igor Erjavec, Antonio Cipcic, Ivica Grgurevic, Dunja Rogic, Kresimir Galesic, Jelena Brkljacic, Ranka Stern-Padovan, Vishwas M Paralkar, Slobodan Vukicevic
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 22 Issue 4 Pg. 681-92 (Apr 2011) ISSN: 1533-3450 [Electronic] United States
• PMID: 21415150 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2011 by the American Society of Nephrology

Chemical References

• BMP7 protein, human
• Bone Morphogenetic Protein 2
• Bone Morphogenetic Protein 3
• Bone Morphogenetic Protein 7
• Collagen Type I
• Protein Isoforms
• Transforming Growth Factor beta1
• beta Catenin
• Bone Morphogenetic Protein 1

Topics

• Adult
• Aged
• Animals
• Bone Morphogenetic Protein 1 (blood)
• Bone Morphogenetic Protein 2 (blood)
• Bone Morphogenetic Protein 3 (blood)
• Bone Morphogenetic Protein 7 (metabolism)
• Cells, Cultured
• Chronic Disease
• Collagen Type I (metabolism)
• Disease Models, Animal
• Female
• Fibrosis
• HEK293 Cells
• Humans
• Kidney (metabolism, pathology)
• Kidney Diseases (metabolism, pathology)
• Male
• Middle Aged
• Protein Isoforms (metabolism)
• Rats
• Rats, Sprague-Dawley
• Transforming Growth Factor beta1 (metabolism)
• beta Catenin (metabolism)