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What are the new milestones in the pathogenesis of systemic sclerosis?
  1. N Hunzelmann1,
  2. J Brinckmann2
  1. 1
    Department of Dermatology, University of Cologne, Köln, Germany
  2. 2
    Department of Dermatology, University of Luebeck, Luebeck, Germany
  1. Correspondence to Professor N Hunzelmann, Department of Dermatology, University of Cologne, Kerpener Str 62, 50924 Köln, Germany; nico.hunzelmann{at}


Systemic sclerosis (SSc) is a chronic inflammatory autoimmune disease involving the connective tissue of the skin and various internal organs. In recent years research on SSc has evolved to provide a better understanding of the interdependence of the three major systems involved—namely, the vascular system, the immune system and the connective tissue. Hypoxia is increasingly recognised as a decisive factor in modulating the inflammatory process in SSc, activating fibroblasts and changing their phenotype. In addition, several mediators synthesised by immune cells, including cytokines such as transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF), cooperate in inducing the activation of fibroblasts and their differentiation into myofibroblasts. Therefore, a variety of intracellular and extracellular strategies to inhibit the activity of TGFβ and PDGF are currently receiving intense investigation. To further improve our therapeutic strategies for this paradigmatic fibrotic disease, an improved understanding of connective tissue remodelling as it takes place in the different stages of SSc will be imperative.

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Systemic sclerosis (SSc) is a rare, severe autoimmune disease involving the connective tissue of the skin and internal organs, resulting in a high morbidity and mortality. The disease is characterised by a remarkable heterogeneity of the disease course and the affected organs in the individual patient.1 2 The disease hallmark is an overproduction and accumulation of collagen and other extracellular matrix (ECM) proteins, resulting in thickening of the skin and fibrosis of the affected organs—for example, the gastrointestinal tract, lung, heart and kidney. The dominant pathophysiological processes, and this perception has essentially not changed over the past 20 years, are an involvement of the vascular system and an activation of the immune system culminating in activation of the connective tissue. This leads in later stages of the disease to a cell poor fibrosis of the affected organs, which may eventually cause severe organ failure.

Role of the immune system in the pathogenesis

SSc is generally perceived as a complex, heterogeneous polygenic disease. Many genetic association studies of genes presumably involved in autoimmune diseases and inflammation have been conducted in patients with SSc. Associations have been described for the HLA region; cytokines—for example, interleukin (IL) 1β, IL2; surface molecules—for example, CD45, CD19; transcription factors such as STAT4;3 4 5 6 7 as well as components of the connective tissue—for example, SPARC and fibrillin.8 9 These reports have not uncommonly yielded conflicting results, which may in part be due to different ethnic backgrounds and the heterogeneity of the disease.

Characteristic autoantibodies targeting nuclear antigens are one of the hallmarks of the disease in about two-thirds of patients with SSc. These antibodies have been shown to constitute a prognostic factor for the disease course and organ involvement, with Scl-70 and centromere proteins as the most prominent autoantigens. Despite intense and detailed studies, no direct involvement in the pathogenesis of these autoantibodies has been demonstrated to date. The central role of the immune system is underlined by the impressive improvements observed after stem cell transplantation in patients with the most severe rapidly progressing form of the disease. The remission of fibrosis after stem cell transplantation is most obvious in the skin but it may also include internal organs such as the lung within weeks to months after treatment.10 11 The mechanisms of this striking improvement are not well understood. Interestingly, characteristic antinuclear antibodies are still detectable after clinically successful treatment in some patients.

Recently, the concept of autoantibodies directed to cell surface molecules (eg, growth factor receptors) which after binding induce signal transduction pathways contributing to the pathogenesis of the respective disease has gained renewed interest. Diseases for which this concept is discussed include rejection of renal allografts, hypertrophic cardiomyopathy and SSc which are usually perceived as T-cell dominated diseases.12 13 14 The role of autoantibodies directed to the platelet-derived growth factor receptor (PDGFR) in SSc will be discussed more in detail below.

Connective tissue in SSc: altered ECM composition and transdifferentiation of fibroblasts

It has long been known that the induction of ECM synthesis with collagen I as the marker gene starts in the perivascular areas of the affected tissue. This induction of collagen synthesis is most prominent in the early, rapidly progressive disease forms. In the tissue affected, perivascular infiltrates comprising activated T cells, monocytes and fibroblasts are present.15 16 However, in later stages of the disease, biopsies reveal a rather hypocellular connective tissue. In this respect the histology of SSc is in apparent contrast to the cell-rich fibrocyte infiltration of the affected organs in nephrogenic systemic fibrosis.17 18

It has been increasingly recognised that in addition to the increased synthesis of particular matrix proteins, there is an altered composition and post-translational modification of the ECM. Lysyl hydroxylase 2 (LH2) is a key enzyme involved in the generation of hydroxylysine aldehyde-derived collagen cross-links typically found in bone tissue.19 Interestingly, in SSc fibroblasts and affected SSc skin in vivo a significant upregulation of LH2 was found, while the enzyme was not induced in normal skin.19 20 This result correlated with previously reported increased levels of hydroxylysine aldehyde-derived collagen cross-links which can be detected in the serum of patients21 22 and in the affected tissue.23 Furthermore, when fibroblasts were cultured under hypoxic conditions for several days a marked upregulation of LH2, also in relation to collagen mRNA synthesis, was seen.20 This finding is corroborated by microarray analyses of SSc skin samples,24 25 where a much higher expression of LH2 was found. Of interest, in these studies a marked upregulation was also found of a number of bone and cartilage-associated proteins—for example, collagens X, XI and cartilage oligomeric protein (COMP) have been reported. COMP, which was originally described as a component of cartilage, bone and ligaments, has recently been shown to be present in increased amounts in patient sera and connective tissue.26 27 28 The deposition of molecules which are not organotypic may induce a resistance to remodelling, contributing to the development of fibrosis.

The study of Gardner et al24 also highlighted the well-known phenomenon of heterogeneity of SSc fibroblasts explanted from affected organ biopsy specimens (ie, skin). In vitro, the SSc fibroblasts lose their phenotype of increased collagen synthesis at higher passage numbers (unpublished observation). Downregulation of integrin α1β1 has been described in SSc fibroblasts29; however, to date no surface marker is known which allows the unequivocal identification of the activated SSc fibroblast.

From a clinical point of view the relevance of hypoxia in the pathophysiology of SSc has long been recognised. However, the cellular signalling pathways induced by short-term or long-term hypoxia have only recently been characterised in more detail. Hypoxia has profound effects on vasculogenesis and partly conflicting results have been published on the presence of circulating endothelial progenitor cells, proangiogenic and antiangiogenic factors.30 31 It has also been suggested that mesenchymal stem cells originating in the bone marrow are directed into the connective tissue of affected organs, contributing to the fibrotic pathophysiology.32

In fibroblasts, hypoxia induces the synthesis of a number of proteins involved in ECM remodelling—for example, thrombospondin 1, fibronectin 1, transforming growth factor β (TGFβ)-induced protein.33 Hypoxia has also been shown to induce the synthesis of connective tissue growth factor (CTGF) in dermal fibroblasts, which further augments the fibrotic response.34 Interestingly, hypoxia may also increase the growth factor response to PDGF by increasing the phosphorylation of its respective receptor (Rosenkranz, personal communication). The induction of epithelial–mesenchymal transition, a newly evolving concept for the pathogenesis of fibrosis in the lung and kidney, has also been directly linked to hypoxia35 as well the activity of TGFβ.36 Thus it has been suggested that hypoxia has a central role in altering the composition of the ECM and maintaining the vicious circle of the fibrotic process.

Role of fibrogenic mediators


By regulating cell differentiation and activation, growth factors such as TGFβ and PDGF are of major importance for the development of fibrotic processes. TGFβ is a pluripotent growth factor with a myriad of inhibiting and stimulating activities on proliferation, apoptosis and protein synthesis of epithelial cells, mesenchymal cells and cells of the immune system—for example, monocytes or T cells.37 Intracellular signal transduction of TGFβ binding to its respective receptors is complex involving both Smad-dependent and Smad-independent pathways—for example, Egr-1, c-Abl.38 39 40

TGFβ is among the strongest inducers of collagen synthesis. It suppresses the production of matrix degrading metalloproteinases (MMPs), induces MMP inhibitors, acts as a chemoattractant and induces CTGF, thereby further augmenting the fibrotic response.41 TGFβ supports the transdifferentiation of fibroblasts to myofibroblasts, inducing α-smooth muscle actin expression.42 Interestingly, inhibition of the phosphodiesterase-4 and -5 pathway (an approach which is currently taken in the treatment of pulmonary arterial hypertension) can inhibit this process.43 These myofibroblasts are recognised as indicator cells of fibrotic processes in the lung or kidney. Nearly all cells involved in the pathophysiology of SSc—that is, endothelial cells, fibroblasts, thrombocytes and a variety of immune cells, synthesise TGFβ. Furthermore, increased numbers of TGFβ receptors have been found on fibroblasts of patients with SSc, thereby enhancing the potential cellular response to TGFβ.44 Thus, TGFβ is often perceived as a master regulator of the disease process in many fibrotic diseases and disease models including the pathogenesis of SSc.

Potential role of fibrillin in enhancing the profibrotic activity of TGFβ

A number of animal models including genetically modified mice (ie, TGFβRII k/o; a1β1 k/o; etc) are known which are used to study the pathophysiology of fibrotic processes.45 46 47 Each of these models has its limitations, each reflecting some aspects of the disease better than others. The tight-skin mouse (TSK-1) is characterised by a profound fibrosis of the subdermal tissue, which has been linked to a mutation of the fibrillin gene, resulting in duplication of a gene segment.48 Polymorphisms in the fibrillin gene have also been described in the Choctaw Indian tribe, which is characterised by a remarkably high frequency of patients with a Scl-70-positive diffuse form of SSc.9 Fibrillins are central constituents of 10–12 nm wide microfibrils found in most tissues and are thought to provide a scaffold for the deposition of tropoelastin. Furthermore, fibrillins are involved in the storage and regulation of growth factors such as TGFβ and bone morphogenetic protein (BMP).49 Mutations in the fibrillin-1 gene have been linked to Marfan syndrome and other heritable connective tissue disorders. Interestingly, in the tight-skin mouse, in SSc, in mixed connective tissue disease and the primary pulmonary hypertension syndrome, autoantibodies against short recombinant fragments of fibrillin-1 have been found.50 However, when using correctly folded complete recombinant fibrillin-1 protein in Caucasian patients with SSc, autoantibodies were not detected.51 An explanation for these conflicting results might be that the detected autoantibodies, which are directed against the shorter fragments of fibrillin-1, represent an immune response to proteolytic fragments of fibrillin-1. These fragments could be generated during the remodelling of the connective tissue which accompanies the fibrotic process. During recent years, several proteases including MMP-7 and cathepsin K have been shown to be upregulated in fibrotic processes.52 53

In scleroderma and lung fibrosis tissue, gene array analyses showed increased fibrillin-1 and fibrillin-2 gene expression levels.24 25 An increase of fibrillin-2 expression was also described in pressure-induced kidney injury.54 Fibrillin-2, apart from a putative role in elastogenesis and cell attachment, is involved in matrix deposition, storage and activation of growth factors of the TGFβ superfamily. TGFβ is synthesised as a pro-protein, bound to the latency-associated protein. This complex is secreted from cells bound to a member of the latent transforming growth factor β binding protein (LTBP) family, which in turn interacts with fibrillin-1 and fibrillin-2.55 In human skin, fibrillin-1 is expressed throughout the dermis, whereas fibrillin-2 is only detectable in the basement membrane and vascular area. Recently, we have shown that increased fibrillin-2 expression in fibrotic areas is associated with latency associated protein-TGFβ expression (Brinckmann et al, submitted). Thus, fibrillin-2 could serve as a structural scaffold to store and release TGFβ and thus contribute to maintaining an activation of fibroblasts in the later stages of the cell-poor phase of fibrosis in SSc.

Considering the overwhelming amount of data which imply a central role for TGFβ in the pathophysiology of fibrosis, it is not surprising that a number of strategies to inhibit different checkpoints of the TGFβ pathway have been developed and are currently studied.56 57 In the fibrotic process, however, several other profibrotic mediators in addition to TGFβ are known to have an important role in the fibrotic process, including PDGF, CTGF, IL4, IL13, IL17, monocyte chemoattractant protein-1 (MCP-1), endothelin-1.58 These molecules could, at least in part, take over the profibrotic role of TGFβ as soon as its activity is blocked. It therefore remains to be shown whether from a therapeutic point of view TGFβ assumes such a central role as a master cytokine in the pathogenesis of SSc as has been ascribed to tumour necrosis factor α (TNFα) in the pathogenesis of rheumatoid arthritis.

Platelet-derived growth factor

PDGF, which initially was extensively studied in wound healing, has since been recognised to have an important role in pulmonary arterial hypertension and inflammatory diseases such as atherosclerosis, lung fibrosis and scleroderma.59 PDGF is a dimeric peptide growth factor that is secreted by several cell types, such as thrombocytes, fibroblasts and smooth muscle cells. It is a potent mitogen for cells of mesenchymal and neuroectodermal origin. In addition, PDGF induces migration, differentiation and transformation of various cell types and takes part in the complex regulation of apoptosis and the generation of O2 radicals. PDGF signal transduction occurs via two specific transmembrane receptor-tyrosine kinases, PDGFRα and PDGFRβ, which differ in their signal transduction cascades and biological effects. For instance, activation of the PDGFRα results in phosphorylation of MAP-kinases (Erk 1/2, p38, JNK), activation of ras, induction of “immediate early genes”, such as Egr-1, c-fos, c-jun, etc.59 60 61 In the mouse, conditional activation of PDGFRα leads to a progressive fibrosis in several organs—for example, skin, gastrointestinal system and heart, underlining the role of this pathway in the development of fibrosis.62

Recently, it has been shown that stimulatory autoantibodies against PDGFRα were detectable in the serum of patients with SSc and could have a causal role in the pathogenesis of this disease. These antibodies bind to the receptors, stimulate respective signalling pathways and lead to increased type I collagen gene expression in fibroblasts.14 These stimulatory autoantibodies are not specific for SSc and have also been detected in graft versus host patients.63 To better define the role of these antibodies in the pathophysiology of SSc, these intriguing results will have to be confirmed by other groups.64

The activation of PDGF receptors can be inhibited by “small molecules”, which were designed to inhibit the activity of tyrosine kinases. Among these substances are imatinib, axitinib, sunitinib, dasatinib, sorafenib and nilotinib. These molecules were originally developed for the treatment of oncological diseases, such as chronic myeloid leukaemia and gastrointestinal tumours, to inhibit proliferative signals via blockade of the tyrosine kinases bcr/abl and c-kit. However, owing to their structural properties, these substances are not entirely specific but show variable “cross reactivity” with other tyrosine kinases and their clinical use has expanded rapidly to other solid tumours—for example, renal carcinoma, bronchial carcinoma, etc. Owing to the effective inhibition of pathways involving PDGF signalling, the tyrosine kinase inhibitor imatinib was tested in a mouse model of pulmonary hypertension,65 demonstrating remarkable effects. This has already led to successful use in a number of case reports.66

Along the same lines, Distler et al could demonstrate for the first time that imatinib, which blocks the activity of c-Abl, an important downstream signalling molecule of TGFβ, can reduce the synthesis of ECM proteins as collagen and fibronectin in human dermal fibroblasts.67 This result could also be extended to the in vivo situation of the bleomycin fibrosis model,68 and initial positive clinical observations on its use in patients with SSc have been reported.69 70

Therefore, as outlined above, small molecules—for example, tyrosine kinase inhibitors, appear as attractive therapeutic tools by virtue of at least partially targeting molecular pathways which are central to the signal transduction of several different cellular signals and operative in the fibrotic process of SSc. (For a more detailed review see Distler et al, page 48.71)

In conclusion, the pathogenesis of SSc reflecting current concepts can be envisioned as shown in a simplified scheme in fig 1. On a given heterogeneous genetic background (involving, in particular, genes of the immune system and the connective tissue), one or several, to date unknown, factors induce an inflammatory response. This initial event spreads and induces an activation of the immune system and vascular system. Profibrotic signals which are generated by immune and vascular cells cooperatively activate fibroblasts of the affected tissue. These activated fibroblasts under repeated hypoxic stress and the influence of fibrogenic mediators lose their original organ-derived phenotype and transdifferentiate in the direction of a bone/cartilage like differentiation. Increased deposition of an altered ECM then contributes to perpetuation of the hypoxic state, which may serve as a model to explain the slow, relentlessly progressing fibrosis in many patients.

Figure 1

Pathogenetic model for systemic sclerosis. ECM, extracellular matrix.



  • Competing interests None.

  • Provenance and Peer review Not commissioned; externally peer reviewed

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