Myofibroblast progenitor cells are increased in number in patients with type 1 diabetes and express less bone morphogenetic protein 6: a novel clue to adverse tissue remodelling?

Nguyen, Tri Q.; Chon, Helena; Nieuwenhoven, Frans A. van; Braam, Branko; Verhaar, Marianne C.; Goldschmeding, Roel

doi:10.1007/s00125-006-0172-0

Cited by 39 publications

(41 citation statements)

References 47 publications

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“…20,21 The molecular mechanism of renal fibrosis has not been fully elucidated, but it is considered to be determined by the expression level of TGF␤1. 22 In this study, the reduced fibrosis in CKD rats treated with the BMP1-3 antibody was associated with a Ͼ50% reduction in the circulating level of TGF␤1 and CTGF.…”

Section: Discussionmentioning

confidence: 99%

Circulating Bone Morphogenetic Protein 1–3 Isoform Increases Renal Fibrosis

Grgurević¹,

Maček²,

Healy³

et al. 2011

Journal of the American Society of Nephrology

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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 TGF␤1 and connective tissue growth factor. In HEK293 cells and remnant kidneys, BMP1-3 increased the transcription of collagen type I, TGF␤1, ␤-catenin, and BMP7 via a BMP-and Wnt-independent mechanism that involved signaling through an integrin ␤1 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.

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Section: Discussionmentioning

confidence: 99%

Circulating Bone Morphogenetic Protein 1–3 Isoform Increases Renal Fibrosis

Grgurević¹,

Maček²,

Healy³

et al. 2011

Journal of the American Society of Nephrology

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show abstract

“…Taken together, these data suggest that EPC decline may be one mechanism of defective glomerular repair and renal disease progression in diabetes. In parallel to decrease in endothelial precursors, diabetes causes increase in myofibroblast progenitor cells, which, due to secretion of extracellular matrix components, may contribute to the progressive glomerular obliteration and fibrosis (59).…”

Section: Epcs and Diabetic Nephropathymentioning

confidence: 99%