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Bone morphogenetic protein-3 is a negative regulator of transforming growth factor beta and fibrosis

Emma R Dorris1, David E Phelan1, John Russell2

  • 1School of Medicine, University College Dublin, Dublin, Ireland; National Children's Research Centre, Children's Health Ireland (Crumlin), Dublin, Ireland.

Biochemical and Biophysical Research Communications
|August 16, 2024
PubMed

Insights

Loss of bone morphogenetic protein (BMP-3) is linked to kidney fibrosis. BMP-3 may reverse fibrosis by inhibiting transforming growth factor beta (TGF-β) signaling, offering a potential new therapy.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Nephrology

Background:

  • Fibrosis, characterized by excess extracellular matrix deposition, causes one-third of global deaths.
  • Transforming growth factor beta (TGF-β) pathway inhibition shows antifibrotic effects.
  • Kidney fibrosis involves complex cellular and molecular mechanisms.

Purpose of the Study:

  • Investigate the role of bone morphogenetic protein (BMP-3) in kidney fibrosis.
  • Determine if BMP-3 loss is a core fibrotic mechanism.
  • Evaluate the therapeutic potential of BMP-3 in fibrosis.

Main Methods:

  • Analysis of BMP-3 expression in kidney fibrosis.
  • Assessment of TGF-β effects on BMP3 expression in human fibroblasts.
  • In vitro studies using recombinant human BMP-3 to modulate fibroblast behavior (contraction, migration, invasion).
  • Measurement of collagen cross-linking and lysyl oxidase activity.

Main Results:

  • Loss of BMP-3 is observed in kidney fibrosis, independent of injury type.
  • TGF-β downregulates BMP3 expression in fibroblasts, potentially creating a positive feedback loop.
  • Recombinant BMP-3 counteracted TGF-β-induced fibroblast contraction, migration, and invasion.
  • BMP-3 reduced TGF-β-stimulated collagen cross-linking and lysyl oxidase activity.

Conclusions:

  • Loss of BMP-3 appears to be a central mechanism in kidney fibrosis.
  • BMP-3 modulates fibroblast responses to TGF-β, shifting the balance from fibrosis towards repair.
  • Recombinant BMP-3 presents a promising therapeutic strategy for treating fibrosis.
Keywords:
BMP-3FibrosisLysyl oxidaseTGF-β

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