Fibrosis in systemic sclerosis: emerging concepts and implications for targeted therapy

Abstract

Systemic sclerosis (SSc) is a complex and incompletely understood disease associated with fibrosis in multiple organs. Recent findings identify transforming growth factor-ß (TGF-ß), Wnt ligands, toll-like receptor-mediated signaling, hypoxia, type I interferon, type 2 immune responses and mechanical stress as extracellular cues that modulate fibroblast function and differentiation, and as potential targets for therapy. Moreover, fibrillin-1 has a major role in storing and regulating the bioavailability of TGF-ß and other cytokines, and fibrillin-1 mutations are implicated in a congenital form of scleroderma called stiff skin syndrome. Fibrosis is due not only to the activation of tissue-resident fibroblasts and their transdifferentiation into myofibroblasts, but also the differentiation of bone marrow-derived fibrocytes, and transition of endothelial and epithelial cells, pericytes and adipocytes into activated mesenchymal cells. These responses are modulated by signaling mediators and microRNAs that amplify or inhibit TGF-ß and Wnt signaling. Gain-of-function and loss-of-function abnormalities of these mediators may account for the characteristic activated phenotype of SSc fibroblasts. The nuclear orphan receptor PPAR-γ plays a particularly important role in limiting the duration and intensity of fibroblast activation and differentiation, and impaired PPAR-γ expression or function in SSc may underlie the uncontrolled progression of fibrosis. Identifying the perturbations in signaling pathways, mediators and differentiation programs that are responsible for SSc tissue damage allows their selective targeting. This in turn opens the door for therapies utilizing novel compounds, or drug repurposing by innovative uses of already-approved drugs. In view of the heterogeneous clinical presentation and unpredictable course of SSc, as well as its complex pathogenesis, only robust clinical trials incorporating the judicious application of biomarkers will be able to clarify the clinical utility of these innovative approaches.

Fig. 1

Schematic overview of the cellular and molecular pathways underlying fibrosis in systemic sclerosis. Injury due to virus, autoantibodies, ischemia–reperfusion, toxins causes inflammation, including T cell and macriphage activation and the generation of autoantibodies. Cytokines and growth factors such as TGF-ß and Wnt10b, and reactive oxygen species geenaretyd at the injury cause fibroblast activation and differentiation into myofibroblasts that produce excess amounts of collagen, contract and remodel the connective tissue, and are resistant to elimination by apoptosis. Injury also directly induces transition of pericytes, epithelial and endothelial cells into myofibroblasts, expanding the tissue pool of matrix–synthesizing activated fibroblasts.

Fig. 2

Tissue damage and innate immune signaling transform an orderly self-limited repair into a disorderly sustained fibrogenic process. Following injury, fibroblasts undergo a regulated activation. Once repair has been accomplished, tissue regeneration is complete. When recurrent or sustained injury leads to damage, matrix molecules are fragmented, resident cells die and toll like receptors are up–regulated. This enables activation of toll like receptor–mediated innate immune recognition signaling and sustained fibroblast activation culminating in excessive fibrogenesis.