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

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.

Transforming growth factor–β in tissue fibrosis

“…The ED-A splice variant of fibronectin (ED-A Fn) is markedly up-regulated in fibrotic tissues and contributes to TGF-β activation by immobilizing LTBPs into the matrix, thus localizing activatable TGF-β in the area of injury (Klingberg et al, 2018;Serini et al, 1998). TSP-1, a multidomain matricellular protein with a wide range of actions, is markedly induced in fibrotic tissues (Frangogiannis, 2012) and has been suggested to act as a crucial activator of TGF-β in some (Murphy-Ullrich and Suto, 2018;Belmadani et al, 2007;Daniel et al, 2003;Xia et al, 2011), but not all, models of tissue fibrosis (Evrard et al, 2011;Gonzalez-Quesada et al, 2013). The TGF-β-activating effects of TSP-1 are mediated through an interaction with LAP that prevents new formation of LAP:TGF-β latent complexes, thus increasing the availability of mature TGF-β that can be bound to its receptors (Schultz-Cherry et al, 1994;Ribeiro et al, 1999).…”

Thrombospondin 1 and Its Diverse Roles as a Regulator of Extracellular Matrix in Fibrotic Disease

“…[19][20][21][22] Small peptides of the TSP1-activating sequence (KRFK) or of the TGF-β latency-associated peptide (LSKL) were used as probes to either mimic or inhibit TSP1-dependent TGF-β activation as a means of assessing the relevance of the TSP1-TGF-β pathway in vitro and in multiple animal models of disease. 5,[23][24][25][26] This function is specific to the TSP1 family member as thrombospondin-2 (TSP2) can bind to the latent complex but lacks the KRFK activation sequence, and the thrombospondin (TSP) type B subfamily members lack the type 1 repeat region that contains the KRFK and WxxW TGF-β binding sequences. 19 A detailed discussion of the mechanism and cellular variations by which TSP1 activates latent TGF-β was recently published.…”

“…174 It is becoming more widely appreciated that interventions that block disease-specific mechanisms of latent TGFβ activation, such as blocking TSP1 or integrin-dependent activation, are likely to have a greater therapeutic index than more broadly targeted antagonists. 26,173,175 Interestingly, some reports suggest that certain integrins can regulate TSP1 expression. In a corneal wound model that deals with fibrosis, knockout of the β 6 integrin delayed initial healing and fibrosis and reduced TSP1 levels; however, TSP1 expression increased later in healing and was associated with α-SMApositive cells.…”

The Increase of pFAK and THBS1 Protein and Gene Expression Levels in Vascular Smooth Muscle Cells by Histamine-treated M1 Macrophages

“…30 It participates in the inflammatory process, but its role in the process of atherosclerosis is not well-known. 31 It can be said, THBS1 increased the processes of VSMCs proliferation and migration in neointima formation. 32 Also, due to its effect on increasing the proliferation of VSMCs, it has been described as a proatherogenic agent.…”