The extracellular matrix and transforming growth factor-β1: Tale of a strained relationship

Matrix Biol. 2015 Sep;47:54-65. doi: 10.1016/j.matbio.2015.05.006. Epub 2015 May 8.

Abstract

Physiological tissue repair aims at restoring the mechano-protective properties of the extracellular matrix. Consequently, redundant regulatory mechanisms are in place ensuring that tissue remodeling terminates once matrix homeostasis is re-established. If these mechanisms fail, stromal cells become continuously activated, accumulate excessive amounts of stiff matrix, and fibrosis develops. In this mini-review, I develop the hypothesis that the mechanical state of the extracellular matrix and the pro-fibrotic transforming growth factor (TGF)-β1 cooperate to regulate the remodeling activities of stromal cells. TGF-β1 is stored in the matrix as part of a large latent complex and can be activated by cell contractile force that is transmitted by integrins. Matrix straining and stiffening lower the threshold for TGF-β1 activation by increasing the mechanical resistance to cell pulling. Different elements of this mechanism can be pharmacologically targeted to interrupt the mechanical positive feedback loop of fibrosis, including specific integrins and matrix protein interactions.

Keywords: Fibronectin; Fibrosis; Latency associated peptide (LAP); Latent TGF-β1 binding protein (LTBP-1); Strain.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Adhesion
  • Extracellular Matrix / physiology*
  • Humans
  • Integrins / physiology
  • Mechanotransduction, Cellular*
  • Transforming Growth Factor beta1 / physiology*

Substances

  • Integrins
  • Transforming Growth Factor beta1