Vascular alterations upon activation of TGFβ signaling in fibroblasts - implications for systemic sclerosis

Tissue fibrosis and vascular disease are hallmarks of systemic sclerosis (SSc). Transforming growth factor β (TGFβ) is a key-player in fibroblast activation and tissue fibrosis in SSc. In contrast to fibrosis, evidence for a role of TGFβ in vascular disease of SSc is scarce. Using a transgenic mouse model with fibroblast-specific expression of a kinase-deficient TGFβ receptor type II, Derrett-Smith and colleagues demonstrate that aberrant TGFβ signaling in fibroblasts might result in activation of vascular smooth muscle cells and architectural changes of the vessel wall of the aorta

The scientific basis for novel treatments of systemic sclerosis

In recent years, many potential antifibrotic treatment strategies have emerged from molecular studies of systemic sclerosis. Few biologicals have already entered clinical trials and these may hopefully prove to be effective in this progressive, profibrotic disease

Hypoxia. Hypoxia in the pathogenesis of systemic sclerosis

Autoimmunity, microangiopathy and tissue fibrosis are hallmarks of systemic sclerosis (SSc). Vascular alterations and reduced capillary density decrease blood flow and impair tissue oxygenation in SSc. Oxygen supply is further reduced by accumulation of extracellular matrix (ECM), which increases diffusion distances from blood vessels to cells. Therefore, severe hypoxia is a characteristic feature of SSc and might contribute directly to the progression of the disease. Hypoxia stimulates the production of ECM proteins by SSc fibroblasts in a transforming growth factor-β-dependent manner. The induction of ECM proteins by hypoxia is mediated via hypoxia-inducible factor-1α-dependent and -independent pathways. Hypoxia may also aggravate vascular disease in SSc by perturbing vascular endothelial growth factor (VEGF) receptor signalling. Hypoxia is a potent inducer of VEGF and may cause chronic VEGF over-expression in SSc. Uncontrolled over-expression of VEGF has been shown to have deleterious effects on angiogenesis because it leads to the formation of chaotic vessels with decreased blood flow. Altogether, hypoxia might play a central role in pathogenesis of SSc by augmenting vascular disease and tissue fibrosis

Long noncoding RNA H19X is a key mediator of TGF-beta-driven fibrosis

TGFβ is a master regulator of fibrosis, driving the differentiation of fibroblasts into apoptosis resistant myofibroblasts and sustaining the production of extracellular matrix (ECM) components. Here, we identify the nuclear lncRNA H19X as a master regulator of TGFβ-driven tissue fibrosis. H19X was consistently upregulated in a wide variety of human fibrotic tissues and diseases and was strongly induced by TGFβ, particularly in fibroblasts and fibroblast-related cells. Functional experiments following H19X silencing revealed that H19X is an obligatory factor for the TGFβ-induced ECM synthesis as well as differentiation and survival of ECM-producing myofibroblasts. We showed that H19X regulates DDIT4L gene expression, specifically interacting with a region upstream of DDIT4L gene and changing the chromatin accessibility of a DDIT4L enhancer. These events resulted in transcriptional repression of DDIT4L and, in turn, in increased collagen expression and fibrosis. Our results shed light on key effectors of the TGFβ-induced ECM remodeling and fibrosis

Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group

To assess the effects of Rituximab (RTX) on skin and lung fibrosis in patients with systemic sclerosis (SSc) belonging to the European Scleroderma Trial and Research (EUSTAR) cohort and using a nested case-control design.status: publishe

Levels of target activation predict antifibrotic responses to tyrosine kinase inhibitors

OBJECTIVES: To assess whether the discrepancy between the strong antifibrotic effects of tyrosine kinase inhibitors (TKIs) in animal models and the inconsistent results in clinical studies might be related to the activation levels of drug targets. METHODS: Skin sections of bleomycin, TSK1, Fra-2 transgenic mice, SSc patients and controls were analysed by histology and immunohistochemistry. Subgroups of mice were treated with the TKIs nilotinib or imatinib. Differences in the activation levels of the TKI targets p-PDGFRβ (platelet derived growth factor β) and p-c-abl were assessed. RESULTS: In bleomycin and TSK1 mice, expression of activated p-PDGFRβ (platelet derived growth factor receptor β) and p-c-abl was ubiquitous with strong upregulation compared with controls. Treatment with TKIs resulted in successful target inhibition and consequently reduced dermal fibrosis. In the Fra-2 model, the activation levels of p-PDGFRβ and p-c-abl were much lower than in the bleomycin and the TSK1 models. Accordingly, nilotinib did not prevent dermal fibrosis and target inhibition was unsuccessful. Notably, in skin biopsies of SSc patients, the mean activation levels of TKI targets were only moderate and in the majority of patients resembled those of the non-responsive Fra-2 model. CONCLUSIONS: Animal models for proof-of-concept studies should be selected based on a similar activation level and expression pattern of drug targets as in human SSc

Activation of liver X receptors inhibits experimental fibrosis by interfering with interleukin-6 release from macrophages

OBJECTIVES: To investigate the role of liver X receptors (LXRs) in experimental skin fibrosis and evaluate their potential as novel antifibrotic targets. METHODS: We studied the role of LXRs in bleomycin-induced skin fibrosis, in the model of sclerodermatous graft-versus-host disease (sclGvHD) and in tight skin-1 (Tsk-1) mice, reflecting different subtypes of fibrotic disease. We examined both LXR isoforms using LXRα-, LXRβ- and LXR-α/β-double-knockout mice. Finally, we investigated the effects of LXRs on fibroblasts and macrophages to establish the antifibrotic mode of action of LXRs. RESULTS: LXR activation by the agonist T0901317 had antifibrotic effects in bleomycin-induced skin fibrosis, in the sclGvHD model and in Tsk-1 mice. The antifibrotic activity of LXRs was particularly prominent in the inflammation-driven bleomycin and sclGvHD models. LXRα-, LXRβ- and LXRα/β-double-knockout mice showed a similar response to bleomycin as wildtype animals. Low levels of the LXR target gene ABCA-1 in the skin of bleomycin-challenged and control mice suggested a low baseline activation of the antifibrotic LXR signalling, which, however, could be specifically activated by T0901317. Fibroblasts were not the direct target cells of LXRs agonists, but LXR activation inhibited fibrosis by interfering with infiltration of macrophages and their release of the pro-fibrotic interleukin-6. CONCLUSIONS: We identified LXRs as novel targets for antifibrotic therapies, a yet unknown aspect of these nuclear receptors. Our data suggest that LXR activation might be particularly effective in patients with inflammatory disease subtypes. Activation of LXRs interfered with the release of interleukin-6 from macrophages and, thus, inhibited fibroblast activation and collagen release

Nintedanib in patients with systemic sclerosis-associated interstitial lung disease: subgroup analyses by autoantibody status and skin score

OBJECTIVE We used data from the SENSCIS trial to assess the effects of nintedanib versus placebo in subgroups of patients with SSc-ILD based on characteristics associated with progression of SSc-ILD in previous studies. METHODS Patients with SSc-ILD were randomized to receive nintedanib or placebo, stratified by anti-topoisomerase I antibody (ATA) status. We assessed the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks in subgroups by baseline ATA status, modified Rodnan skin score (mRSS) (<18 versus ≥18), and SSc subtype (limited cutaneous SSc [lcSSc] versus diffuse cutaneous SSc [dcSSc]). RESULTS At baseline, of 576 patients treated, 60.8% were ATA-positive, 51.9% had dcSSc, and 77.5% of 574 patients with mRSS data available had mRSS 0.05 for all). CONCLUSION In patients with SSc-ILD, no heterogeneity was detected in the treatment effect of nintedanib in reducing the annual rate of decline in FVC across subgroups based on ATA status, mRSS, and SSc subtype