Systemic sclerosis: a prototypic multisystem fibrotic disorder

Abstract

A unique feature of systemic sclerosis (SSc) that distinguishes it from other fibrotic disorders is that autoimmunity and vasculopathy characteristically precede fibrosis. Moreover, fibrosis in SSc is not restricted to a single organ, but rather affects many organs and accounts for much of the morbidity and mortality associated with this disease. Although immunomodulatory drugs have been used extensively in the treatment of SSc, no therapy to date has been able to reverse or slow the progression of tissue fibrosis or substantially modify the natural progression of the disease. In this Review, we highlight recent studies that shed light on the cellular and molecular mechanisms underlying the fibrotic process in SSc and that identify cellular processes and intra- and extracellular proteins as potential novel targets for therapy in this prototypic multisystemic fibrotic disease.

Figure 1. Pathogenesis of SSc: integration of vasculopathic and immunological processes leading to fibrosis.

The pathogenesis of SSc is initiated by microvascular injury (i). This induces inflammation and autoimmunity (ii), which have direct and indirect roles in inducing fibroblast activation (iii), a key event in the development of fibrosis. The number of fibroblasts and their precursors in affected tissues is increased by trafficking as well as by the differentiation of mesenchymal cells (iv). Activated myofibroblasts in the lesional tissue perform a series of functions culminating in fibrosis (v). MSC, mesenchymal stem cell.

Figure 2. Skin inflammation and fibrosis in SSc.

(A) In early diffuse cutaneous SSc, moderate fibrosis in the upper dermis and at the dermal-epidermal junction is accompanied by evidence of keratinocyte hypertrophy with a flattening of the epidermis, leading to loss of reticular structure and decreased length of rete pegs (fingerlike structures that project up from the dermis and down from the epidermis, increasing the area of contact between the layers of the skin). In addition, inflammatory infiltrates are found in the dermis and near the dermal-epidermal junction, predominantly around small blood vessels. (B) Early-stage diffuse disease showing profound dermal inflammation characterized by perivascular mononuclear cellular infiltrate composed of monocytes and activated lymphocytes, with perivascular fibrosis and loss of pericytes and vessel integrity. (C) In established fibrosis, collagen accumulation leads to dermal thickening and the deposition of dense and closely packed collagen fibers throughout the dermis, with the loss of the microvasculature and dermal structures and the dermis-subcutaneous adipose tissue interface. All images are stained with H&E and photographed using a Zeiss Axioscope confocal microscope under light field. Original magnification, ×100 (A and C); ×200 (B).

Figure 3. Profibrotic signaling by TGF-β through SMAD-dependent pathways.

The ECM serves as a reservoir for latent TGF-β, which is maintained in an inactive form by latent TGF-β binding proteins (LTBPs). Upon activation, TGF-β binds to its cell surface receptors and triggers SMAD-mediated intracellular signal transduction. Activated SMAD proteins accumulate in the nucleus and bind to conserved SBE regulatory elements in target genes, recruit coactivators and chromatin-modifying enzymes such as p300/CBP to the DNA, and induce mRNA synthesis and cellular responses. Inhibitory SMAD7 blocks ligand-induced SMAD protein phosphorylation and shuts down SMAD-mediated signaling.

Figure 4. TGF-β signaling through non-SMAD pathways.

Receptor activation by TGF-β can cause activation of non-SMAD pathways involved in regulating cell proliferation, cytoskeletal rearrangement, ECM synthesis, and apoptosis. Activation of intracellular protein and lipid kinase cascades results in activation of DNA-binding transcription factors and regulation of gene expression. These signal transdution pathways might converge on or interact with the canonical SMAD pathway or operate completely independent of SMAD pathways. AP-1, acivator protein 1; EGR-1, early growth response 1; PAK2, p21-activated kinase 2; ROCK, Rho-associated, coiled-coil containing protein kinase 1; TAB1/2, TAK1-binding protein 1/2; TAK1, TGF-β activated kinase 1.