Thrombospondin-1 regulation of latent TGF-β activation: A therapeutic target for fibrotic disease

Matrix Biol. 2018 Aug;68-69:28-43. doi: 10.1016/j.matbio.2017.12.009. Epub 2017 Dec 27.

Abstract

Transforming growth factor-β (TGF-β) is a central player in fibrotic disease. Clinical trials with global inhibitors of TGF-β have been disappointing, suggesting that a more targeted approach is warranted. Conversion of the latent precursor to the biologically active form of TGF-β represents a novel approach to selectively modulating TGF-β in disease, as mechanisms employed to activate latent TGF-β are typically cell, tissue, and/or disease specific. In this review, we will discuss the role of the matricellular protein, thrombospondin 1 (TSP-1), in regulation of latent TGF-β activation and the use of an antagonist of TSP-1 mediated TGF-β activation in a number of diverse fibrotic diseases. In particular, we will discuss the TSP-1/TGF-β pathway in fibrotic complications of diabetes, liver fibrosis, and in multiple myeloma. We will also discuss emerging evidence for a role for TSP-1 in arterial remodeling, biomechanical modulation of TGF-β activity, and in immune dysfunction. As TSP-1 expression is upregulated by factors induced in fibrotic disease, targeting the TSP-1/TGF-β pathway potentially represents a more selective approach to controlling TGF-β activity in disease.

Keywords: Anti-fibrotic; Diabetic nephropathy; Fibrosis; Latent TGF-β; TGF-β; Thrombospondin-1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Diabetes Complications / drug therapy
  • Diabetes Complications / metabolism
  • Fibrosis / drug therapy*
  • Fibrosis / metabolism
  • Humans
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / metabolism
  • Multiple Myeloma / complications
  • Multiple Myeloma / metabolism
  • Peptides / pharmacology
  • Peptides / therapeutic use
  • Thrombospondin 1 / antagonists & inhibitors
  • Thrombospondin 1 / metabolism*
  • Transforming Growth Factor beta / metabolism*

Substances

  • Leu-Ser-Lys-Leu peptide
  • Peptides
  • Thrombospondin 1
  • Transforming Growth Factor beta
  • thrombospondin-1, human