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Systemic sclerosis (SSc) is an autoimmune connective tissue disease with a triad of features that include vascular abnormalities, inflammation and skin and lung fibrosis. At the core of the disease is the activation of myofibroblasts from quiescent fibroblasts and this can be modified by various cytokines. IL-41 is a recently described cytokine that was initially characterised as an adipokine as it was highly expressed in adipocytes and adipose tissue. However, it has recently been identified as being widely expressed and has immunomodulatory functions. This study examined the circulating levels of IL-41 and its expression in skin biopsies. We demonstrated significantly reduced levels of IL-41 in diffuse SSc that was also mirrored in the skin of SSc patients. AMPK has been proposed as a downstream target of IL-41, so we also measure mammalian target of rapamycin in skin and found that this is elevated in SSc patients. We speculate that IL-41 maybe an antifibrotic cytokine and its reduction may facilitate the activation of fibroblasts. [ABSTRACT FROM AUTHOR]

Systemic sclerosis is an autoimmune connective tissue disease which is characterised by vascular perturbations, inflammation, and fibrosis. Although huge progress recently into the underlying molecular pathways that are perturbed in the disease, currently no therapy exists that targets the fibrosis element of the disease and consequently there is a huge unmet medical need. Emerging studies reveal new dimensions of complexity, and multiple aberrant pathways have been uncovered that have shed light on disturbed signalling in the disease, primarily in inflammatory pathways that can be targeted with repurposed drugs. Pre-clinical animal models using these inhibitors have yielded proof of concept for targeting these signalling systems and progressing to clinical trials. This review will examine the recent evidence of new perturbed pathways in SSc and how these can be targeted with new or repurposed drugs to target a currently intractable disease. [ABSTRACT FROM AUTHOR]

Summary: Interleukin-11 is a cytokine from the IL-6 family of cytokines that includes IL-6 and oncostatin-M. Initially described for its role in platelet generation, it is now appreciated that this cytokine has multiple functions. Recently it has been found that IL-11 is critical in fibrosis in multiple different organ systems and systemically as in the autoimmune disease systemic sclerosis. Animal models of fibrosis have determined that animals with IL-11 receptor deletions have retarded fibrosis and that in wild-type animals IL-11 is found at the organ of fibrosis. Recent evidence suggests that IL-11 may be a master regulator of fibrosis regardless of end target organ. With the development of neutralizing antibodies targeting the cytokine in pre-clinical models this could be a possible therapeutic, in a disease in which no specific therapies exist. This review appraises the evidence of the role of IL-11 in tissue fibrosis, its signalling properties, and therapeutic targeting. The review ends with an appraisal of indications for which IL-11 modulation is targeted. IL-11 is a key IL-6 family cytokine that has recently been associated with tissue fibrosis. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is an autoimmune connective tissue disease in which there is elevated inflammation, aberrant cytokine expression, and subsequent fibrosis. Interleukin‐11 (IL‐11) is a recently described profibrotic cytokine that can mediate fibrosis in the heart, lungs, and skin and is upregulated by transforming Growth Factor‐β (TGF‐β1). The objective of this study was to quantify the serum levels of IL‐11 in early diffuse SSc patients. Also, if IL‐11 could regulate the alarmin IL‐33 in dermal fibroblasts was quantified. Early diffuse SSc patient sera was isolated and IL‐11 was quantified by specific commercial ELISA compared to healthy control (n = 17). Healthy dermal fibroblasts were cultured in vitro and then serum starved and incubated with or without recombinant IL‐11. At specific early and late time points the supernatant was quantified for the alarmin IL‐33 by specific ELISA. In early diffuse SSc patients it was demonstrated that they have elevated IL‐11 in their sera. In a subgroup of SSc patients with interstitial lung disease (ILD) this elevation was particularly pronounced compared to those devoid of fibrotic lung disease. In vitro incubation of healthy dermal fibroblasts led to a significant induction of IL‐33 cytokine release into the cell media. IL‐11 is a profibrotic cytokine that is elevated in early diffuse SSc and is particularly elevated in those with ILD. This suggests that IL‐11 could be a possible biomarker of ILD in SSc. It was also found that IL‐11 led to release of the cytokine alarmin IL‐33 in fibroblasts at earlier time points but not late time points, suggesting early stimulation elicits an inflammatory response in the local microenvironment but prolonged stimulation leads to fibrosis. [ABSTRACT FROM AUTHOR]

SSc is an autoimmune disease that has features of vascular abnormalities, inflammation and skin and lung fibrosis. Toll-like receptors (TLRs) are sentinel receptors that serve to recognize pathogens or internal danger signals leading to downstream signalling pathways that ultimately lead to inflammation and modification of adaptive immunity. Inflammation and fibrosis appear intricately connected in this disease and TLR ligation on fibroblasts can directly activate these cells to produce copious amounts of collagen, a hallmark of disease. The presence of damage-associated molecular patterns in association with fibrosis has been highlighted. Given their prominent role in disease, this review discusses the evidence of their expression and role in disease pathogenesis and possible therapeutic intervention to mitigate fibrosis. [ABSTRACT FROM AUTHOR]

Gremlin-1 is part of the TGF-β superfamily and is a BMP antagonist that blocks BMP signalling to precisely control BMP gradients. Gremlin-1 is primarily involved in organogenesis and limb patterning however, has recently been described as being involved in fibrotic diseases. Initially described as a key factor involved in diabetic kidney fibrosis due to being induced by high glucose, it has now been described as being associated with lung, liver, eye, and skin fibrosis. This suggests that it is a key conserved molecule mediating fibrotic events irrespective of organ. It appears that Gremlin-1 may have effects mediated by BMP-dependent and independent pathways. The aim of this review is to evaluate the role of Gremlin-1 in fibrosis, its mechanisms and if this can be targeted therapeutically in fibrotic diseases, which currently have very limited treatment options and are highly prevalent. [ABSTRACT FROM AUTHOR]

Objectives Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with activation of human dermal fibroblasts (HDFs) from patients with SSc or controls. Methods We measured serum IL11 levels in volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches that we combined with molecular and cellular phenotyping. Results In patients with SSc, serum IL11 levels are elevated as compared with healthy controls. All transforming growth factor beta (TGFβ) isoforms induced IL11 secretion from HDFs, which highly express IL11 receptor α-subunit and the glycoprotein 130 (gp130) co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation and extracellular matrix secretion. The pro-fibrotic action of IL11 in HDFs appeared unrelated to STAT3 activity, independent of TGFβ upregulation and was not associated with phosphorylation of SMAD2/3. Inhibition of IL11 signalling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacological inhibition of ERK. Conclusions These data reveal that autocrine IL11-dependent ERK activity alone or downstream of TGFβ stimulation promotes fibrosis phenotypes in dermal fibroblasts and suggest IL11 as a potential therapeutic target in SSc. [ABSTRACT FROM AUTHOR]

The metabolic shift that cancer cells undergo towards aerobic glycolysis was identified as a defining feature in tumours almost 100 years ago; however, it has only recently become apparent that similar metabolic reprogramming is a key feature in other diseases – with fibrosis now entering the fray. In this perspective, an overview of the recent evidence implicating increased glycolysis and glutaminolysis as mediators of fibrosis is presented, with a particular emphasis on the novel therapeutic possibilities this introduces. Furthermore, the impact that metabolic reprogramming has on redox homeostasis is discussed, providing an insight into how this often-overlooked mechanism may drive the pathogenesis. Metabolism has emerged as a major driver of fibrotic diseases. Glycolytic shifts appear to be a key metabolic switch in stromal cells under fibrotic conditions regardless of aetiology. Glutaminolysis as well as glycolysis may be a therapeutic target in fibrosis. Immunometabolites exert antifibrotic effects and may be harnessed for therapeutic gain. [ABSTRACT FROM AUTHOR]

Systemic Sclerosis (SSc) is an autoimmune connective tissue disease that leads to skin and lung fibrosis. The Wnt pathway is clearly elevated in SSc and is pro-fibrotic via activation of canonical Wnt signalling. sFRP-1 is a Wnt antagonist that acts as a negative regulator of Wnt signalling. We sought to measure the levels of serum sFRP-1 in early diffuse SSc patients compared to healthy controls and if this is regulated by microRNA27a-3p. Ten early diffuse SSc patients and healthy controls sera were taken and sFRP-1 quantified by ELISA. Skin biopsies were also taken in five SSc patients and controls. Fibroblasts were quantified for microRNA27-3p expression by Taqman qRT-PCR with an internal microRNA to normalize. 3ʹUTR luciferase assays were performed to confirm direct targets of microRNA27a-3p with microRNA overexpression. Fibroblasts were transfected with microRNA27a mimics or scramble controls and using ELISA sFRP-1 was quantified. Furthermore, Collagen, Axin-2, TIMP-1 and MMP-1 were measured. Serum sFRP-1 was significantly reduced in early diffuse SSc patients. We identified microRNA27a-3p-3p as regulating sFRP-1 in dermal fibroblasts. We found significantly elevated microRNA27a-3p in isolated dermal fibroblasts from SSc patients. We confirmed that sFRP-1 is a direct target of microRNA27a-3p through cloning of the 3ʹUTR into a luciferase vector. ECM genes were also upregulated by microRNA27a-3p-3p and the matrix-degrading enzyme MMP-1 was suppressed. Serum sFRP-1 is reduced in diffuse SSc patients and is regulated by microRNA27a-3p and this is a direct regulation. Modulation of microRNA27a-3p levels could mediate fibrosis regression. [ABSTRACT FROM AUTHOR]

Background: Systemic sclerosis is an autoimmune skin disease which is associated with inflammation and resulting skin fibrosis. Myofibroblasts are the key cell type associated with the fibrosis but how they are differentiated is not clear. DKK‐1 is a Wnt antagonist that blocks Wnt‐mediated fibrosis and is reduced in fibrotic conditions. Thus, DKK‐1 is a clear negative regulator of fibrosis in systemic sclerosis and its regulation is unknown. The aim of this work is to determine the levels of DKK‐1 in serum and tissues of SSc and its regulation. Methods: Skin biopsies were taken from early diffuse systemic sclerosis patients and healthy controls and DKK‐1 measured by ELISA; serum was also isolated and DKK‐1 quantified. DKK‐1 was also measured by qRT‐PCR. MicroRNA33a‐3p was measured by TaqMan PCR. miR mimics and controls were transfected into dermal fibroblasts. Bleomycin mouse model was employed and compared to vehicle control treated mice, and gene expression was employed for DKK‐1 and various extracellular matrix genes. Results: DKK‐1 is reduced in SSc skin and fibroblasts but is not reduced in the circulation in patients. MicroRNA33a‐3p regulates DKK‐1 levels epigenetically and is significantly reduced in SSc cells and whole tissue. DKK‐1 is also reduced in the bleomycin mouse model and pro‐fibrotic genes elevated. Conclusion: DKK‐1 is reduced in SSc cells and is regulated by miR33a‐3p, and restoring DKK‐1 levels through epigenetic means could be a therapeutic target in systemic sclerosis. [ABSTRACT FROM AUTHOR]

Systemic Sclerosis (SSc) is a rare fibrotic autoimmune disorder for which no curative treatments currently exist. Metabolic remodelling has recently been implicated in other autoimmune diseases; however, its potential role in SSc has received little attention. Here, we aimed to determine whether changes to glycolysis and glutaminolysis are important features of skin fibrosis. TGF‐β1, the quintessential pro‐fibrotic stimulus, was used to activate fibrotic pathways in NHDFs in vitro. Dermal fibroblasts derived from lesions of SSc patients were also used for in vitro experiments. Parameters of glycolytic function were assessed using by measuring extracellular acidification in response to glycolytic activators/inhibitors, whilst markers of fibrosis were measured by Western blotting following the use of the glycolysis inhibitors 2‐dg and 3PO and the glutaminolysis inhibitor G968. Succinate was also measured after TGF‐β1 stimulation. Itaconate was added to SSc fibroblasts and collagen examined. TGF‐β1 up‐regulates glycolysis in dermal fibroblasts, and inhibition of glycolysis attenuates its pro‐fibrotic effects. Furthermore, inhibition of glutamine metabolism also reverses TGF‐β1‐induced fibrosis, whilst glutaminase expression is up‐regulated in dermal fibroblasts derived from SSc patient skin lesions, suggesting that enhanced glutamine metabolism is another aspect of the pro‐fibrotic metabolic phenotype in skin fibrosis. TGF‐β1 was also able to enhance succinate production, with increased succinate shown to be associated with increased collagen expression. Incubation of SSc cells with itaconate, an important metabolite, reduced collagen expression. TGF‐β1 activation of glycolysis is a key feature of the fibrotic phenotype induced by TGF‐B1 in skin cells, whilst increased glutaminolysis is also evident in SSc fibroblasts. [ABSTRACT FROM AUTHOR]

Objectives NF-κB regulates genes that control inflammation, cell proliferation, differentiation and survival. Dysregulated NF-κB signalling alters normal skin physiology and deletion of cRel limits bleomycin-induced skin fibrosis. This study investigates the role of cRel in modulating fibroblast phenotype in the context of SSc. Methods Fibrosis was assessed histologically in mice challenged with bleomycin to induce lung or skin fibrosis. RNA sequencing and pathway analysis was performed on wild type and Rel −/− murine lung and dermal fibroblasts. Functional assays examined fibroblast proliferation, migration and matrix production. cRel overexpression was investigated in human dermal fibroblasts. cRel immunostaining was performed on lung and skin tissue sections from SSc patients and non-fibrotic controls. Results cRel expression was elevated in murine lung and skin fibrosis models. Rel −/− mice were protected from developing pulmonary fibrosis. Soluble collagen production was significantly decreased in fibroblasts lacking cRel while proliferation and migration of these cells was significantly increased. cRel regulates genes involved in extracellular structure and matrix organization. Positive cRel staining was observed in fibroblasts in human SSc skin and lung tissue. Overexpression of constitutively active cRel in human dermal fibroblasts increased expression of matrix genes. An NF-κB gene signature was identified in diffuse SSc skin and nuclear cRel expression was elevated in SSc skin fibroblasts. Conclusion cRel regulates a pro-fibrogenic transcriptional programme in fibroblasts that may contribute to disease pathology. Targeting cRel signalling in fibroblasts of SSc patients could provide a novel therapeutic avenue to limit scar formation in this disease. [ABSTRACT FROM AUTHOR]

Objective: In systemic sclerosis (SSc), a persistent tissue repair process leads to progressive fibrosis of the skin and internal organs. The role of mesenchymal stem cells (MSCs), which characteristically initiate and regulate tissue repair, has not been fully evaluated. We undertook this study to investigate whether dividing metakaryotic MSCs are present in SSc skin and to examine whether exposure to the disease microenvironment activates MSCs and leads to transdifferentiation. Methods: Skin biopsy material from patients with recent‐onset diffuse SSc was examined by collagenase spread of 1‐mm–thick surface‐parallel sections, in order to identify dividing metakaryotic stem cells in each tissue plane. Adipose‐derived MSCs from healthy controls were treated with dermal blister fluid (BF) from patients with diffuse SSc and profiled by next‐generation sequencing, or they were evaluated for phenotypic changes relevant to SSc. Differential responses of dermal fibroblasts were studied in parallel. Results: MSC‐like cells undergoing active metakaryotic division were identified in SSc sections (but not control sections) most prominently in the deep dermis and adjacent to damaged microvessels, in both clinically involved and uninvolved skin. Furthermore, exposure to SSc BF caused selective MSC activation, inducing a myofibroblast signature, while reducing signatures of vascular repair and adipogenesis and enhancing migration and contractility. Microenvironmental factors implicated in inducing transdifferentiation included the profibrotic transforming growth factor β, the presence of lactate, and mechanosensing, while the microenvironment Th2 cytokine, interleukin‐31, enhanced osteogenic commitment (calcinosis). Conclusion: Dividing MSC‐like cells are present in the SSc disease microenvironment where multiple factors, likely acting in concert, promote transdifferentiation and lead to a complex and resistant disease state. [ABSTRACT FROM AUTHOR]

Recreating the structure of human tissues in the laboratory is valuable for fundamental research, testing interventions, and reducing the use of animals. Critical to the use of such technology is the ability to produce tissue models that accurately reproduce the microanatomy of the native tissue. Current artificial cell‐based skin systems lack thorough characterisation, are not representative of human skin, and can show variation. In this study, we have developed a novel full thickness model of human skin comprised of epidermal and dermal compartments. Using an inert porous scaffold, we created a dermal construct using human fibroblasts that secrete their own extracellular matrix proteins, which avoids the use of animal‐derived materials. The dermal construct acts as a foundation upon which epidermal keratinocytes were seeded and differentiated into a stratified keratinised epithelium. In‐depth morphological analyses of the model demonstrated very close similarities with native human skin. Extensive immunostaining and electron microscopy analysis revealed ultrastructural details such as keratohyalin granules and lamellar bodies within the stratum granulosum, specialised junctional complexes, and the presence of a basal lamina. These features reflect the functional characteristics and barrier properties of the skin equivalent. Robustness and reproducibility of in vitro models are important attributes in experimental practice, and we demonstrate the consistency of the skin construct between different users. In summary, a new model of full thickness human skin has been developed that possesses microanatomical features reminiscent of native tissue. This skin model platform will be of significant interest to scientists researching the structure and function of human skin. [ABSTRACT FROM AUTHOR]

Objective SSc is an autoimmune connective tissue disease that results in skin fibrosis and currently has no effective treatment. Epigenetic modifications have been described and these may be key in initiating and driving fibroblast activation. Among these epigenetic modifications methylation may be of central importance. The aim of this study was to examine the role of methyl cap binding protein-2 (MeCP2) in SSc fibrosis. Methods We used healthy and SSc dermal fibroblasts to examine the role of MeCP2, using both small interfering RNA silencing and lentiviral overexpression to determine its effects. We also examined the expression of MeCP2 in SSc fibroblasts by immunoblotting. miRNA132 was quantified by Taqman real time PCR. Results We demonstrated that TGF-β1 induced the expression of MeCP2 in normal cells, and showed that SSc fibroblasts expressed high levels of MeCP2 under basal conditions. MeCP2 positively regulated the expression of extracellular matrix through epigenetic repression of the Wnt antagonist sFRP-1, leading to enhanced Wnt signalling. This mediated fibrosis through glycolysis, as the glycolysis inhibitor 2-deoxyglucose diminished the Wnt-mediated collagen expression. MiR132 expression was reduced in SSc fibroblasts. Conclusion The results suggest that an epigenetic loop exists mediating fibrosis. Targeting of MeCP2, as a key epigenetic regulator, may be a promising therapeutic approach, as would targeting the metabolic reprogramming that occurs through aerobic glycolysis. [ABSTRACT FROM AUTHOR]

SSc is an autoimmune idiopathic disease in which there is an inflammatory component driving fibrosis. The chief cell involved is the myofibroblast, which when activated secretes copious amounts of extracellular matrix that forms deposits, leading to stiffness and fibrosis. The fibrosis is most prevalent in the skin and lungs. In recent years epigenetic modifications have been uncovered that positively and negatively regulate the genesis of the myofibroblasts and that can be activated and regulated by a variety of cytokines and hormones. The epigenetic contribution to these cells and to SSc is only now really coming to light, and this opens up a new therapeutic target for the disease for which many epigenetic drugs, such as miRNA replacements, are beginning to be developed. This review will examine the epigenetic regulators in the disease and possible targeting of these. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation is a curative treatment for numerous hematological malignancies. However, acute graft-versus-host disease (aGvHD) is a major complication affecting 40–70% of all transplant patients, whereby the earliest and most frequent presentation is in the skin. MicroRNAs play a role in varied biological process and have been reported as potential biomarkers for aGvHD. More recently, microRNAs have received added attention as circulatory biomarkers that can be detected in biofluids. In this study, we performed global microRNA expression profiling using a discovery cohort of diagnostic cutaneous aGvHD biopsies (n = 5, stages 1–3) and healthy volunteers (n = 4), in order to identify a signature list of microRNAs that could be used as diagnostic biomarkers for cutaneous aGvHD. Candidate microRNAs (n = 8) were then further investigated in a validation cohort of post-HSCT skin biopsies (n = 17), pre-HSCT skin biopsies (n = 6) and normal controls (n = 6) for their association with aGvHD. Expression of let-7c (p = 0.014), miR-503-5p (p = 0.003), miR-365a-3p (p = 0.02), miR-34a-5p (p < 0.001) and miR-34a-3p (p = 0.006) were significantly differentially expressed between groups and significantly associated with survival outcome in post-HSCT patients (miR-503-5p ROC AUC = 0.83 p = 0.021, Log Rank p = 0.003; miR-34a-3p ROC AUC = 0.93, p = 0.003, Log Rank p = 0.004). There was no association with relapse. A statistical interaction between miR-34a-3p and miR-503-5p (p = 0.016) was diagnostic for aGvHD. Expression levels of the miR-34a-5p protein target p53 were assessed in the epidermis of the skin, and an inverse correlation was identified (r2 = 0.44, p = 0.039). Expression of the validated candidate microRNAs was also assessed at day 28 post-HSCT in the sera of transplant recipients, in order to investigate their potential as circulatory microRNA biomarkers. Expression of miR-503-5p (p = 0.001), miR-34a-5p (p = 0.005), and miR-34a-3p (p = 0.004) was significantly elevated in the sera of patients who developed aGvHD versus no-aGvHD (n = 30) and miR-503-5p was associated with overall survival (OS) (ROC AUC = 0.80, p = 0.04, Log Rank p = 0.041). In conclusion, this investigation reports that microRNA expression levels in clinical skin biopsies, obtained at the time of cutaneous aGvHD onset, show potential as diagnostic biomarkers for aGvHD and as predictive biomarkers for OS. In addition, the same microRNAs can be detected in the circulation and show predictive association with post-HSCT outcomes. [ABSTRACT FROM AUTHOR]

Pattern Recognition Receptors are critical receptors that elicit an immune response upon their activation that culminates in activation of NF-KB and cytokine secretion. Key among these receptors are the Toll-Like Receptors (TLRs). These evolutionary conserved receptors form a key part in the defence against various pathogens and comprise a key part of the innate immune system. Systemic sclerosis is an autoimmune disease in which a breach of tolerance has occurred and leads to fulminant autoimmunity, dysregulated cytokines, pro-fibrotic mediators and activation of fibroblasts leading to fibrosis via collagen deposition. It has become apparent in recent years that the innate immune system and specifically TLRs are important in disease pathogenesis; responding to internal ligands to initiate an innate immune response ultimately leading to release of a variety of factors that initiate and perpetuate fibrosis. This review will examine the recent evidence of TLR signalling in systemic sclerosis and the internal danger associated molecules that may mediate the fibrotic cascade. Evaluation of their contribution to disease in systemic sclerosis and possible therapeutic targeting will be discussed. [ABSTRACT FROM AUTHOR]

Background/Aims: The Trabecular meshwork (TM) is the tissue responsible for outflow resistance and therefore intraocular pressure. TM cells contain a contractile apparatus that is composed of actin stress fibres which run parallel to the axis of the cell and are responsible for facilitating contraction. Cross-Linked Actin Networks (CLANs) are polygonal arrangements of actin that form a geodesic network found predominantly in TM cells both in situ and in vitro. The aim of this work is to determine the functional significance of CLANs in TM cells and to assess the effect of mechanical stretch stimulation on the induction (or not) of CLANs. Methods: We used collagen gel contraction models to demonstrate functional impairment of cells when induced to express CLANs in situ. Cyclic mechanical stretch was used to stimulate cells and measure CLANs Results: CLANs inhibited contraction and cyclic mechanical stretch induced CLANs. Furthermore, we also demonstrated that using shape alone we could predict the appearance of CLANs using a simple light microscopy technique. Conclusion: Taken together we have now shown, for the first time, a functional deficit In TM cells with CLANs Furthermore that shape alone can predict the appearance of CLAN containing cells. CLANs can now be linked to a functional effect and may underlie the appearance of CLANs with the pathology of primary open angle glaucoma (POAG). [ABSTRACT FROM AUTHOR]

The skin is the largest organ of the integumentary system and possesses a vast number of functions. Due to the distinct layers of the skin and the variety of cells which populate each, a tightly regulated network of molecular signals control development and regeneration, whether due to programmed cell termination or injury. MicroRNAs (miRs) are a relatively recent discovery; they are a class of small non-coding RNAs which possess a multitude of biological functions due to their ability to regulate gene expression via post-transcriptional gene silencing. Of interest, is that a plethora of data demonstrates that a number of miRs are highly expressed within the skin, and are evidently key regulators of numerous vital processes to maintain non-aberrant functioning. Recently, miRs have been targeted as therapeutic interventions due to the ability of synthetic ‘antagomiRs’ to down-regulate abnormal miR expression, thereby potentiating wound healing and attenuating fibrotic processes which can contribute to disease such as systemic sclerosis (SSc). This review will provide an introduction to the structure and function of the skin and miR biogenesis, before summarizing the literature pertaining to the role of miRs. Finally, miR therapies will also be discussed, highlighting important future areas of research. [ABSTRACT FROM AUTHOR]

Fibrosis is a common and important disease. It is a pathological state due to excessive scar formation mediated by an increase in activated fibroblasts that express alpha smooth muscle actin and copious amounts of extracellular matrix molecules. Epigenetics is an area of research that encompasses three main mechanisms: methylation, histone modifications to the tails of histones and also non-coding RNAs including long and short non-coding RNAs. These three mechanisms all seek to regulate gene expression without a change in the underlying DNA sequence. In recent years an explosion of research, aided by deep sequencing technology becoming available, has demonstrated a role for epigenetics in fibrosis, either organ specific like lung fibrosis or more widespread as in systemic sclerosis. While the great majority of epigenetic work in fibrosis is centered on histone codes, more recently the non-coding RNAs have been examined in greater detail. It is known that one modification can affect the other and cross-talk among all three adds a new layer of complexity. This review aims to examine the role of epigenetics in fibrosis, evaluating all three mechanisms, and to suggest possible areas where epigenetics could be targeted therapeutically. [ABSTRACT FROM AUTHOR]

Fibrosis is characterised by an exuberant wound healing response and the major cell type responsible is the myofibroblast. The myofibroblast is typified by excessive ECM production and contractile activity and is demarcated by alpha-smooth muscle actin expression. What has recently come to light is that the activation of the fibroblast to myofibroblast may be under epigenetic control, specifically methylation. Methylation of DNA is a conserved mechanism to precisely regulate gene expression in a specific context. Hypermethylation leads to gene repression and hypomethylation results in gene induction. Methylation abnormalities have recently been uncovered in fibrosis, both organ specific and widespread fibrosis. The fact that these methylation changes are rapid and reversible lends themselves amenable to therapeutic intervention. This review considers the role of methylation in fibrosis and the activation of the myofibroblasts and how this could be targeted for fibrosis. Fibrosis is of course currently intractable to therapeutics and is a leading cause of morbidity and mortality and is an urgent unmet clinical need. [ABSTRACT FROM AUTHOR]