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

Transforming growth factor-beta (TGF-beta) is a central player in fibrotic disease. Clinical trials with global inhibitors of TGF-beta have been disappointing, suggesting that a more targeted approach is warranted. Conversion of the latent precursor to the biologically active form of TGF-beta represents a novel approach to selectively modulating TGF-beta in disease, as mechanisms employed to activate latent TGF-beta 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-beta activation and the use of an antagonist of TSP-1 mediated TGF-beta activation in a number of diverse fibrotic diseases. In particular, we will discuss the TSP-1TIGF-beta 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-beta activity, and in immune dysfunction. As TSP-1 expression is upregulated by factors induced in fibrotic disease, targeting the TSP-1/TGF-beta pathway potentially represents a more selective approach to controlling TGF-beta activity in disease. (C) 2018 Elsevier B.V. All rights reserved.