COL1A1 proximal promoter topology regulates its transcriptional response to transforming growth factor β.

Objective: The COL1A1 proximal promoter contains two GC-rich regions and two inverted CCAAT boxes. The transcription factors Sp1 and CBF bind to the GC sequence at -122 to -115 bp and the inverted CCAAT box at -101 to -96 bp, respectively, and stimulate COL1A1 transcriptional activity.

Methods: To further define the regulatory mechanisms controlling COL1A1 expression by Sp1 and CBF, we introduced 2, 4, 6, or 8 thymidine nucleotides (T-tracts) at position -111 bp of the COL1A1 gene promoter to increase the physical distance between these two binding sites and examined the transcriptional activities of the resulting constructs and their response to TGF-β1.

Cellular Transdifferentiation: A Crucial Mechanism of Fibrosis in Systemic Sclerosis.

Systemic Sclerosis (SSc) is a systemic autoimmune disease of unknown etiology with a highly complex pathogenesis that despite extensive investigation is not completely understood. The clinical and pathologic manifestations of the disease result from three distinct processes: 1) Severe and frequently progressive tissue fibrosis causing exaggerated and deleterious accumulation of interstitial collagens and other extracellular matrix molecules in the skin and various internal organs; 2) extensive fibroproliferative vascular lesions affecting small arteries and arterioles causing tissue ischemic alterations; and 3) cellular and humoral immunity abnormalities with the production of numerous autoantibodies, some with very high specificity for SSc. The fibrotic process in SSc is one of the main causes of disability and high mortality of the disease.

Pharmacological treatment of systemic sclerosis-associated interstitial lung disease: an updated review and current approach to patient care.

Interstitial lung disease (ILD) has a high prevalence among patients with systemic sclerosis (SSc), carrying high mortality and morbidity. During the last decade, the emergence of new pharmacological therapies for SSc-associated ILD (SSc-ILD) and improved tools for its diagnosis and monitoring have changed the prevailing clinical approach, highlighting the need for early recognition and prompt treatment for SSc-ILD. Furthermore, the recent approval of multiple therapies for SSc-ILD poses challenges for the rheumatologist and pulmonologist in choosing the appropriate therapy for individual clinical scenarios.

Aptamer proteomics of serum exosomes from patients with Primary Raynaud's and patients with Raynaud's at risk of evolving into Systemic Sclerosis.

Background: A major unmet need for Systemic Sclerosis (SSc) clinical management is the lack of biomarkers for the early diagnosis of patients with Raynaud's Phenomenon at high risk of evolving into SSc.

Objective: To identify proteins contained within serum exosomes employing an aptamer proteomic analysis that may serve to reveal patients with Raynaud's Phenomenon at risk of developing SSc.

Methods: Exosomes were isolated from serum samples from patients with Primary Raynaud's Phenomenon and from patients with Raynaud's Phenomenon harbouring serum antinuclear antibodies (ANA) who may be at high risk of evolving into SSc.

Treatment of Severe Swallowing Dysfunction in Systemic Sclerosis with IVIG: Role of Antimuscarinic Antibodies.

Oropharyngeal and esophageal dysmotility can cause serious clinical complications such as aspiration pneumonia, cachexia, and sarcopenia, with a resulting increase in mortality and disability. The current standard of care for the treatment of SSc-associated swallowing dysfunction is mainly supportive, although severe cases are usually refractory to conventional management. Recent studies have shown that the abnormal production of functional autoantibodies such as anti-cholinergic muscarinic receptor III antibodies may participate in the pathogenesis of SSc-associated gastrointestinal dysmotility and may provide a novel target for therapeutic intervention.

Probable role of exosomes in the extension of fibrotic alterations from affected to normal cells in systemic sclerosis.

SSc is a systemic autoimmune disease of unknown etiology characterized by frequently progressive cutaneous and internal organ fibrosis causing severe disability, organ failure and high mortality. A remarkable feature of SSc is the extension of the fibrotic alterations to nonaffected tissues. The mechanisms involved in the extension of fibrosis have remained elusive.

Progressive multifocal fibrosing neuropathy: description of a novel disease.

Entrapment peripheral neuropathies are clinically characterized by sensory impairment and motor deficits. They are usually caused by mechanical injuries, but they are also a frequent manifestation of metabolic diseases, toxic agent exposure, or systemic fibrotic disorders. Here we describe the clinical, radiological, and histopathological features of a novel progressive fibrotic disorder characterized by progressive multifocal fibrosing neuropathy.

Oxidative Stress Induced by Reactive Oxygen Species (ROS) and NADPH Oxidase 4 (NOX4) in the Pathogenesis of the Fibrotic Process in Systemic Sclerosis: A Promising Therapeutic Target.

Numerous clinical and research investigations conducted during the last two decades have implicated excessive oxidative stress caused by high levels of reactive oxygen species (ROS) in the development of the severe and frequently progressive fibrotic process in Systemic Sclerosis (SSc). The role of excessive oxidative stress in SSc pathogenesis has been supported by the demonstration of increased levels of numerous biomarkers, indicative of cellular and molecular oxidative damage in serum, plasma, and other biological fluids from SSc patients, and by the demonstration of elevated production of ROS by various cell types involved in the SSc fibrotic process. However, the precise mechanisms mediating oxidative stress development in SSc and its pathogenetic effects have not been fully elucidated.

Serine/threonine kinase inhibition as antifibrotic therapy: transforming growth factor-β and Rho kinase inhibitors.

Serine/threonine kinases mediate the phosphorylation of intracellular protein targets, transferring a phosphorus group from an adenosine triphosphate molecule to the specific amino acid residues within the target proteins. Serine/threonine kinases regulate multiple key cellular functions. From this large group of kinases, TGF-β through serine/threonine activity of its receptors and Rho kinase (ROCK) play an important role in the development and maintenance of fibrosis in various human diseases, including SSc.

Global gene expression analysis of systemic sclerosis myofibroblasts demonstrates a marked increase in the expression of multiple NBPF genes.

Myofibroblasts are the key effector cells responsible for the exaggerated tissue fibrosis in Systemic Sclerosis (SSc). Despite their importance to SSc pathogenesis, the specific transcriptome of SSc myofibroblasts has not been described. The purpose of this study was to identify transcriptome differences between SSc myofibroblasts and non-myofibroblastic cells.

Tyrosine kinases in the pathogenesis of tissue fibrosis in systemic sclerosis and potential therapeutic role of their inhibition.

Systemic sclerosis (SSc) is an idiopathic autoimmune disease with a heterogeneous clinical phenotype ranging from limited cutaneous involvement to rapidly progressive diffuse SSc. The most severe SSc clinical and pathologic manifestations result from an uncontrolled fibrotic process involving the skin and various internal organs. The molecular mechanisms responsible for the initiation and progression of the SSc fibrotic process have not been fully elucidated.

Increased expression of interferon regulated and antiviral response genes in CD31+/CD102+ lung microvascular endothelial cells from systemic sclerosis patients with end-stage interstitial lung disease.

Objectives: Systemic sclerosis (SSc) is characterised by severe fibroproliferative vasculopathy, fibrosis in skin and multiple internal organs, and humoral, cellular and innate immunity abnormalities. Vascular alterations are the earliest and most severe SSc manifestations, however, the mechanisms responsible have remained elusive. To investigate the molecular abnormalities involved in SSc-vasculopathy we examined global gene expression differences between highly purified lung microvascular endothelial cells (MVECs) from patients with SSc-interstitial lung disease (SSc-ILD) and normal lung MVECs.

Molecular characteristics and functional differences of anti-PM/Scl autoantibodies and two other distinct and unique supramolecular structures known as "EXOSOMES".

The term "exosome" has been applied to three distinct supramolecular entities, namely the PM/Scl autoantibodies or "RNA exosomes", transforming DNA fragments termed "DNA exosomes", and small size extracellular vesicles knows as "exosomes". Some of the molecular components of the "PM/Scl exosome complex" or "RNA exosome" are recognized by specific autoantibodies present in the serum from some Systemic Sclerosis (SSc), polymyositis (PM) and polymyositis SSc (PM/Scl) overlap syndrome patients. On the other hand, one of the most active focuses of laboratory investigation in the last decade has been the biogenesis and role of extracellular vesicles known as "exosomes".

Increased expression of the transforming growth factor β-inducible gene HIC-5 in systemic sclerosis skin and fibroblasts: a novel antifibrotic therapeutic target.

Objective: SSc is a systemic fibrotic disease affecting skin, numerous internal organs and the microvasculature. The molecular pathogenesis of SSc tissue fibrosis has not been fully elucidated, although TGF-β1 plays a crucial role. The Hic-5 protein encoded by the TGF-β1-inducible HIC-5 gene participates in numerous TGF-β-mediated pathways, however, the role of Hic-5 in SSc fibrosis has not been investigated.

Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH.

Background: Systemic sclerosis (SSc) is characterised by autoimmune activation, tissue and vascular fibrosis in the skin and internal organs. Tissue fibrosis is driven by myofibroblasts, that are known to maintain their phenotype in vitro, which is associated with epigenetically driven trimethylation of lysine 27 of histone 3 (H3K27me3).

Methods: Full-thickness skin biopsies were surgically obtained from the forearms of 12 adult patients with SSc of recent onset.

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study.

Objectives: Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.

Methods: SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.

Role of microRNA in the pathogenesis of systemic sclerosis tissue fibrosis and vasculopathy.

Systemic Sclerosis (SSc) pathogenesis involves multiple immunological, vascular and fibroproliferative abnormalities that contribute to a severe and complex clinical picture. Vasculopathy and fibroproliferative alterations are two hallmark pathological processes in SSc that are responsible for the most severe clinical manifestations of the disease and determine its clinical outcome and mortality. However, the pathogenesis of SSc vasculopathy and of the uncontrolled SSc fibrotic process remain incompletely understood.

Recurrence of progressive skin involvement following discontinuation or dose reduction of Mycophenolate Mofetil treatment in patients with diffuse Systemic Sclerosis.

Background: Rapidly progressive diffuse cutaneous Systemic Sclerosis (rp-dcSSc) is associated with severe internal organ involvement and high mortality. Mycophenolate Mofetil (MMF) has been shown to halt the progression of rp-dcSSc cutaneous and pulmonary involvement in observational and randomized controlled trials, respectively. However, optimal MMF therapy duration has not been established.

Endothelial to Mesenchymal Transition: Role in Physiology and in the Pathogenesis of Human Diseases.

Numerous studies have demonstrated that endothelial cells are capable of undergoing endothelial to mesenchymal transition (EndMT), a newly recognized type of cellular transdifferentiation. EndMT is a complex biological process in which endothelial cells adopt a mesenchymal phenotype displaying typical mesenchymal cell morphology and functions, including the acquisition of cellular motility and contractile properties. Endothelial cells undergoing EndMT lose the expression of endothelial cell-specific proteins such as CD31/platelet-endothelial cell adhesion molecule, von Willebrand factor, and vascular-endothelial cadherin and initiate the expression of mesenchymal cell-specific genes and the production of their encoded proteins including α-smooth muscle actin, extra domain A fibronectin, N-cadherin, vimentin, fibroblast specific protein-1, also known as S100A4 protein, and fibrillar type I and type III collagens.

Abrogation of transforming growth factor-β-induced tissue fibrosis in mice with a global genetic deletion of Nox4.

Excessive connective tissue deposition in skin and various internal organs is characteristic of systemic sclerosis (SSc). The profibrotic growth factor TGF-β plays a crucial role in SSc pathogenesis. The expression of NADPH oxidase 4 (NOX4), a critical mediator of oxidative stress, is potently stimulated by TGF-β.

Simultaneous inhibition of c-Abl and Src kinases abrogates the exaggerated expression of profibrotic genes in cultured systemic sclerosis dermal fibroblasts.

Objectives: To examine the effects of simultaneous inhibition of c-Abl and Src kinases on the gene expression and in vitro production of profibrotic molecules by dermal fibroblasts from patients with diffuse systemic sclerosis (SSc) of recent onset.

Methods: Dermal fibroblasts from normal individuals or from patients with diffuse cutaneous SSc fulfilling the American College of Rheumatology/EULAR SSc classification criteria were cultured in media containing increasing concentrations of the dual c-Abl and Src kinase inhibitor Bosutinib for 24 h. Total soluble collagen in cell culture supernatants was quantified.

Existing and novel biomarkers for precision medicine in systemic sclerosis.

The discovery and validation of biomarkers resulting from technological advances in the analysis of genomic, transcriptomic, lipidomic and metabolomic pathways involved in the pathogenesis of complex human diseases have led to the development of personalized and rationally designed approaches for the clinical management of such disorders. Although some of these approaches have been applied to systemic sclerosis (SSc), an unmet need remains for validated, non-invasive biomarkers to aid in the diagnosis of SSc, as well as in the assessment of disease progression and response to therapeutic interventions. Advances in global transcriptomic technology over the past 15 years have enabled the assessment of microRNAs that circulate in the blood of patients and the analysis of the macromolecular content of a diverse group of lipid bilayer membrane-enclosed extracellular vesicles, such as exosomes and other microvesicles, which are released by all cells into the extracellular space and circulation.