BMP7 antagonizes TGF-β-dependent fibrogenesis in mesangial cells

Abstract

Exogenous administration of recombinant human bone morphogenetic protein (BMP)-7 was recently shown to ameliorate renal glomerular and interstitial fibrosis in rodents with experimental renal diseases. We tested the hypothesis that BMP7 functions by antagonizing profibrogenic events that are induced by transforming growth factor (TGF)-β in cultured mesangial cells. Incubation of murine mesangial cells with TGF-β (50–200 pM) increased cell-associated collagen type IV and fibronectin, soluble collagen type IV, thrombospondin, and connective tissue growth factor (CTGF). Coincubation with recombinant human BMP7 (200 pM) reduced the increase of these ECM proteins and CTGF. The changes in collagen type IV and fibronectin proteins occurred without concomitant changes in collagen type α1IV and fibronectin mRNA levels, suggesting that TGF-β and BMP7 act primarily by affecting ECM protein degradation. Indeed, TGF-β decreases the levels and activity of matrix metalloprotease (MMP)-2, the major metalloprotease that is secreted by mesangial cells. Moreover, BMP7 inhibits TGF-β-induced activation of MMP2. Because TGF-β reduces the activity of MMPs through increasing plasminogen activator inhibitor (PAI)-1, we tested whether BMP7 interferes with this TGF-β effect. BMP7 reduces, by about two-thirds, the activation of a PAI-1 promoter/luciferase reporter in cells stably transfected with this construct. The findings from these studies indicate that BMP7 reduces TGF-β-induced ECM protein accumulation in cultured mesangial cells primarily by maintaining levels and activity of MMP2 partially through prevention of TGF-β-dependent upregulation of PAI-1.

BMP-7 Modulates Hyaluronan-Mediated Proximal Tubular Cell-Monocyte Interaction

“…In vitro studies shed some further light on the mechanistic basis of the mode of action of BMP-7. In mesangial cells, it reduces TGF-␤1-induced extracellular matrix effects (41). Specific membrane-bound high-affinity BMP-7 receptors have also been characterized on adult rat kidney tubular cells (42), and in vitro in PTC, BMP-7 antagonizes TNF-␣-stimulated increases in expression of proinflammatory cytokines and chemokines (43).…”

Enhanced expression of bone morphogenetic protein system in aldosterone-treated mouse kidneys

“…12,25 BMP-7 treatment also resolves glomerular and interstitial fibrosis in rats with diabetic nephropathy, 25 which results from inhibition of the TGF-b effects on fibrosis mediators and matrix protein-degrading enzymes. 13 In this regard, BMP-7 antagonizes TGF-b-induced glomerular fibrogenesis such as connective tissue growth factor expression and accumulation of collagen, fibronectin and thrombospondin in cultured mouse mesangial cells, suggesting that BMP-7 inhibits several profibrogenic activities of TGF-b in mesangial cells. 13 Renal TGF-b expression is elevated in mineralocorticoid-salt hypertension 26 or in Aldo-dependent remnant kidney model.…”

“…13 In this regard, BMP-7 antagonizes TGF-b-induced glomerular fibrogenesis such as connective tissue growth factor expression and accumulation of collagen, fibronectin and thrombospondin in cultured mouse mesangial cells, suggesting that BMP-7 inhibits several profibrogenic activities of TGF-b in mesangial cells. 13 Renal TGF-b expression is elevated in mineralocorticoid-salt hypertension 26 or in Aldo-dependent remnant kidney model. 27 Considering that the renal TGF-b production is provoked by Aldo effects, 27 BMPs may have an antagonistic role in Aldo-induced TGF-b actions leading to amelioration of glomerular sclerosis.…”

“…11 In experimental animal nephropathy, BMP-7 has been known to ameliorate fibrotic changes of renal tissues by antagonizing TGF-b-induced profibrogenic activities. 12,13 It is also reported that BMP-4 and BMP-7 are highly expressed in prospective podocytes and parietal epithelial cells of developing glomeruli, suggesting that BMP may have a role in glomerulogenesis. 14 We previously reported antagonistic effects of BMPs on renal mesangial cell proliferation induced by Aldo in vitro.…”

Therapeutic effects of adenoviral gene transfer of bone morphogenic protein-7 on a corneal alkali injury model in mice

“…Hepatocyte growth factor 27,28 and bone morphogenic protein-7 (BMP-7) [29][30][31][32] are cytokines that antagonize TGF-b activity in tissue fibrosis. BMP-7 utilizes Smad1/5/8 signaling which counteracts TGF-b/Smad signaling by, in part, upregulation of inhibitors of differentiation 2 and 3 (Id2 and Id3).…”