ReviewFibrosis in systemic sclerosis: Emerging concepts and implications for targeted therapy
Introduction
Systemic sclerosis (SSc) is a progressive autoimmune disease of unknown cause associated with substantial mortality. To date there are no disease-modifying therapies, and immunomodulatory agents that are highly effective in other rheumatic diseases have shown disappointing results in SSc. The explanation may lie in the complex nature of SSc, characterized by a constellation of vascular injury, inflammation and fibrosis. It is not clear which of these perturbations is primary. Every SSc patient manifests some degree of vascular injury, immune activation and tissue fibrosis, but the relative contributions of these distinct processes to individual disease phenotype and natural history varies greatly from patient to patient. This variability accounts for the strikingly heterogeneous clinical picture of SSc. The three seemingly disparate yet interrelated pathophysiologic processes account for the clinical manifestations of SSc. Evidence of vascular injury and endothelial damage are detected at initial evaluation in a majority of patients. Over time, progressive vascular damage and obliteration of small and medium sized arteries cause tissue ischemia and its myriad complications. Vascular injury also plays a role in activation of the innate and adaptive immune systems, and contribute directly and indirectly to tissue fibrosis. The interrelationship of the three cardinal processes in the pathogenesis of SSc is illustrated in Fig. 1. In this review we focus on recent exciting developments in understanding fibrosis, the final common pathway in SSc that accounts for much of its mortality.
Section snippets
Skin fibrosis
Skin fibrosis is prominent and widespread in diffuse cutaneous SSc (dcSSc), whereas in limited cutaneous SSc (lcSSc) vascular complications rather than fibrosis tend to predominate. Fibrotic skin is characterized by thick dermis and obliteration of appendages such as hair follicles, sweat glands and cutaneous blood vessels. Initially fibrosis is most prominent in the reticular dermis, but with progression, the subjacent adipose layer also becomes affected. Biochemical analysis of affected skin
Fibroblast activation in SSc
Over three decades ago, Carwile LeRoy demonstrated that lesional skin fibroblasts explanted from patients with SSc synthesize increased amounts of collagen in vitro compared to healthy control fibroblasts [1], [2]. Additional features that phenotypically define SSc fibroblasts include increased synthesis of extracellular matrix; constitutive production of cytokines and chemokines; altered expression of cell surface integrins and receptors for transforming growth factor-ß (TGF-ß),
Cell types and cell fate switching in fibrosis
It is not surprising that a multiplicity of cell types are activated or deregulated in SSc, and play a role in tissue damage. Effector cells prominent at various stages of the disease include endothelial cells and vascular pericytes, cellular components of both the adaptive and innate arms of the immune system (Th2 cells and B lymphocytes, dendritic cells, NK cells, monocytes, alternatively-activated macrophages, mast cells and eosinophils) and possibly plasmacytoid dendritic cells. In the
Persistent fibrotic responses: innate immune recognition signaling via toll-like receptors
Recent studies indicate a potential important role for innate immune signaling via toll-like receptors (TLRs) in fibrosis in SSc. A critical aspect of normal host defence against invading microorganisms is the ability to recognize pathogen-associated molecular patterns. Pattern recognition receptors (PRRs) are the critical cellular sensors for exogenous danger. The family of PRRs includes, in addition to TLRs, lectin receptors, scavenger receptors CD36 and MARCO and complement receptors [7].
Soluble factors and extracellular cues regulating fibroblast activation and differentiation
Transforming growth factor-ß is the pre-eminent cue for initiating connective tissue remodeling during both normal wound healing and pathological fibrosis. The expression of receptors for TGF-ß as well as surface integrins that activate latent TGF-ß are elevated on SSc fibroblasts, suggesting that the SSc phenotype reflects autocrine TGF-ß stimulation of sensitized cells [10]. While recent studies provide support for the “autocrine TGF-ß hypothesis” [11], [12], [13], [14], pharmacological
Peroxisome proliferator-activated receptor-γ: negative regulation of fibroblast activation and differentiation
Peroxisome proliferator-activated receptor gamma (PPAR-γ) directly modulates TGF-ß signaling and mesenchymal cell plasticity, and is increasingly associated with regulation of matrix remodeling and fibrosis. Originally identified in adipocytes, PPAR-γ is a nuclear hormone receptor and ligand-inducible transcription factor with fundamental roles in adipogenesis and lipid metabolism. In the absence of a recognized true physiologic ligand, PPAR-γ is considered to be an orphan receptor. Multiple
Impaired PPAR-γ in fibrosis and SSc: role in pathogenesis
Fibroblast-specific gene targeting of PPAR-γ resulted in markedly exaggerated skin fibrosis when mice were injected with bleomycin [62]. Similarly, PPAR-γ deletion in follicular stem cells in mice causes localized fibrosis that resembles scarring alopecia [63]. On the other hand, we found that treatment with rosiglitazone attenuated bleomycin-induced dermal fibrosis in mice, suggesting a critical physiologic role for PPAR-γ in preventing excessive fibrotic responses. Consistent with this notion
Conclusion
The intractable problem of fibrosis is finally beginning to yield its secrets. Unbiased genome-wide expression analysis using DNA microarrays, population-based genetic association studies and transgenic animal models are contributing to a substantially enhanced understanding of the cellular and molecular basis of fibrosis in SSc. Cell-intrinsic alterations in SSc fibroblasts contribute to their activated phenotype. These include aberrant expression of TGF-ß receptors, activation of downstream
Take-home messages
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SSc is highly heterogeneous in its clinical and autoimmune manifestations; individualized therapy required
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SSc is distinct from other rheumatic diseases; the unique combination of fibrosis and vascular disease is prominent
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because its manifestations and clinical course of SSc are highly heterogeneous, there is an urgent need for the discovery and validation of biomarkers to help classify patients, identify high risk groups, predict drug responders
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There are no effective therapies for reversing or
Acknowledgements
Supported by grants from the National Institutes of Health (AR 42309) and the Scleroderma Research Foundation. We are grateful to our colleagues Gabriella Lakos, Carol Feghali-Bostwick, Monique Hinchcliff, Robert Lafyatis, Michael Whitfield, Guofei Zhou, Cara Gottardi, Anna Lam, Carol Artlett and Maria Trojanowska for helpful comments, and members of the Varga lab for valuable insights.
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