Transforming growth factor beta as a therapeutic target in systemic sclerosis

Abstract

Transforming growth factor beta (TGF-beta) is a pleiotropic cytokine with vital homeostatic functions. Aberrant TGF-beta expression is implicated in the pathogenesis of fibrosis in systemic sclerosis (SSc); thus, TGF-beta represents a molecular therapeutic target in this disease. Anti-TGF-beta monoclonal antibody has been evaluated in a small trial of early SSc, with disappointing results. Antibodies against the alphavbeta6 integrin that prevent latent TGF-beta activation, however, have shown promise in preclinical studies. Small-molecule inhibitors of TGF-beta-receptor activity are effective in animal models of fibrosis. Imatinib mesylate and related tyrosine kinase inhibitors also block TGF-beta pathways and abrogate fibrotic responses. The blocking of TGF-beta activity might lead to spontaneous immune activation, epithelial hyperplasia and impaired wound healing. Loss of immune tolerance is a potential concern in an autoimmune disease such as SSc. Novel insights from microarray-based gene expression analyses and studies of genetic polymorphisms in TGF-beta signaling could aid in identifying patients who are most likely to respond to anti-TGF-beta treatment. This intervention promises to have a major impact on the treatment of SSc. Concerns regarding efficacy and safety and whether biomarkers can indicate these features, questions regarding appropriate dosing and timing of therapy, and identification of potential responders are critical challenges ahead.

Figure 1

Major components of the TGF-ß signaling pathway. TGF-ß secreted from monocytes, macrophages, lymphocytes and fibroblasts is sequestered in the extracellular matrix in a biologically inactive latent form. Latent TGF-ß activation is catalyzed by αvß6 integrin on epithelial cell membranes. Active TGF-ß binds to serine/threonine kinase cell surface receptors that phosphorylate downstream SMAD2/3. Phosphorylated SMAD2/3 complexes with SMAD4 and accumulates within the nucleus, where it collaborates with other trancription factors, and recruits cofactors such as p300 to target genes, resulting in transcription. SMAD7 is a TGF-ß-inducible endogenous SMAD inhibitor that negatively regulates TGF-ß signaling. TGF-ß can also induce cellular responses such as epithelial-mesenchymal transition (EMT) via Smad-independent pathways involving the kinases Jun N-terminal kinase (JNK), p38, phosphoinositide 3 (PI3) kinase, c-Abl and TGF-ß-activated kinase TAK1. The duration of the TGF-ß signal is regulated by the uptake of the TGF-ß receptor–ligand complex into caveolin-lined endosomes that promote degradation. Excessive TGF-ß activity, or deregulated receptor trafficking or intracellular SMAD signaling result in collagen overproduction and fibrosis. Abbreviation TGF- ß, transforming growth factor-ß

Figure 2

Strategies for blocking TGF-ß pathways. Biological therapies targeting TGF-ß are shown in grey boxes; small molecule therapies are shown in yellow boxes. Neutralizing antibodies to αvß6 integrin inhibit latent TGF-ß activation only at sites of injury where αvß6 integrin is expressed. Neutralizing antibodies to TGF-ß sequester the active ligand, and soluble receptor peptides prevent its binding to cell surface receptors. Small molecule kinase inhibitors of type 1 TGF-ß receptor block SMAD2/3 activation and abrogate SMAD-dependent profibrotic responses such as collagen synthesis and myofibroblast transformation. Tyrosine kinase inhibitors such as imatinib mesylate block SMAD-independent intracellular TGF-ß signaling. Abbreviation TGF- ß, transforming growth factor-ß