title: 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.affiliation: Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, Zagreb, Croatia.
authors.forename: Lovorka
authors.initials: L
authors.lastname: Grgurevic
authors.forename: Boris
authors.initials: B
authors.lastname: Macek
authors.forename: David R
authors.initials: DR
authors.lastname: Healy
authors.forename: Amy L
authors.initials: AL
authors.lastname: Brault
authors.forename: Igor
authors.initials: I
authors.lastname: Erjavec
authors.forename: Antonio
authors.initials: A
authors.lastname: Cipcic
authors.forename: Ivica
authors.initials: I
authors.lastname: Grgurevic
authors.forename: Dunja
authors.initials: D
authors.lastname: Rogic
authors.forename: Kresimir
authors.initials: K
authors.lastname: Galesic
authors.forename: Jelena
authors.initials: J
authors.lastname: Brkljacic
authors.forename: Ranka
authors.initials: R
authors.lastname: Stern-Padovan
authors.forename: Vishwas M
authors.initials: VM
authors.lastname: Paralkar
authors.forename: Slobodan
authors.initials: S
authors.lastname: Vukicevic
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D055395:Bone Morphogenetic Protein 1 / Q000097:blood*; D055396:Bone Morphogenetic Protein 2 / Q000097:blood*; D055398:Bone Morphogenetic Protein 3 / Q000097:blood*; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C525819:BMP7 protein, human; D055396:Bone Morphogenetic Protein 2; D055398:Bone Morphogenetic Protein 3; D055419:Bone Morphogenetic Protein 7; D024042:Collagen Type I; D020033:Protein Isoforms; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D055395:Bone Morphogenetic Protein 1