RARE DISEASE
Localized scleroderma
Localized scleroderma
Localized scleroderma
Synonyms: Localized fibrosing scleroderma
Synonyms: Localized fibrosing scleroderma
Synonyms: Localized fibrosing scleroderma
Drug discovery
3
drugs
With orphan designations
Overview
Localized scleroderma (LS) is an autoimmune disorder characterized by collagen overproduction, causing skin fibrosis and inflammation without systemic organ involvement. It presents as morphea (circumscribed plaques) or linear scleroderma (streaks affecting skin, muscle, or bone). While primarily cutaneous, deep tissue involvement may lead to limb asymmetry, joint contractures, or facial deformities. Diagnosis relies on clinical assessment and biopsy confirmation.
Burden
Disability-adjusted life years (DALY) disproportionately affect ages 15–54, driven by chronic disability [4].
Extracutaneous complications (e.g., musculoskeletal, neurological) occur in 20% of pediatric cases [6][19].
Quality-of-life impacts include disfigurement, pain, and fatigue, despite non-life-threatening progression [14][19].
Categories: rare skin diseases
Research Papers
859 drug discovery papers about Localized scleroderma, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
859 drug discovery papers about Localized scleroderma, with 3 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-28 | Spatially resolved gene programs and cell neighborhoods of scleroderma fibroblasts 2261024
Abstract Introduction Systemic sclerosis (SSc, scleroderma) is a chronic autoimmune disease with high mortality, characterized by progressive fibrosis of the skin and internal organs. Skin involvement is among the earliest manifestations of disease, and changes in skin pathology can mirror systemic progression. While single-cell studies have revealed striking transcriptional diversity among dermal fibroblasts in SSc, the spatial organization and immune signals that govern their function remain unclear. Methods To address this, we performed high-resolution spatial transcriptomic profiling of clinically affected and unaffected skin from SSc donors alongside healthy controls. Results We identify known disease-associated fibroblast subsets, including COMP+ myofibroblasts, which localize within cell neighborhoods enriched in activated endothelial and immune cells. In contrast, LGR5+/PI16+ fibroblasts — abundant in healthy skin and previously shown to contain a T cell-inducible gene program — are significantly reduced in both clinically involved and uninvolved SSc skin and occupy distinct microenvironments from disease-associated cells. Conclusion Our findings provide a spatial framework for understanding fibroblast heterogeneity and identify potential therapeutic strategies aimed at reinforcing protective fibroblast programs to prevent or delay fibrosis in scleroderma. Funding Source R21AI185642 NIAID/NIH, National Scleroderma Foundation Topic Categories Immune Mechanisms of Human Disease (HUM)
2026-06-22 | Pioglitazone in Skin Fibrosis: Mechanistic Rationale and Therapeutic Potential of Pioglitazone for Scarring Dermatoses.
Cutaneous fibrosis - encompassing keloids, hypertrophic scars, localized scleroderma (morphea), and scarring alopecias - remains fundamentally undertreated, with conventional interventions frequently yielding incomplete therapeutic responses and high rates of recurrence. Pioglitazone, a Food and Drug Administration (FDA)-approved peroxisome proliferator-activated receptor γ (PPAR-γ) agonist traditionally utilized for glycemic control in type 2 diabetes mellitus, represents a highly compelling candidate for dermatologic repurposing. Beyond its canonical metabolic functions, robust target engagement of PPAR-γ by pioglitazone suppresses NF-κB-driven cytokine cascades, directly inhibits NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome assembly, promotes macrophage polarization toward tissue-reparative phenotypes, and disrupts profibrotic TGF-β/SMAD signaling architectures. Consequently, the drug exerts a dual mechanism of action, simultaneously attenuating chronic inflammation while inhibiting pathological fibrogenesis. This review expands upon prior analyses by integrating recently published clinical and scientific data, specifically highlighting new translational milestones, including human registry data in progeroid syndromes and randomized controlled trials in cicatricial alopecia. A distinct focus is placed on advancements in localized delivery strategies, such as nanostructured lipid carriers and niosomes, that offer the potential to overcome pioglitazone's inherent physicochemical constraints and thereby maximize dermal target engagement while avoiding systemic toxicities like heart failure and bladder cancer. Furthermore, this analysis synthesizes recent molecular insights connecting fibrosis and inflammation via target engagement biomarkers (e.g., FABP4, CD36) and proposes actionable, biomarker-driven trial designs, including adaptive basket trials, to bridge current gaps in dermatology-specific translation. Demonstrating localized anti-fibrotic and anti-inflammatory efficacy with minimal systemic risk could establish pioglitazone as a mechanism-based, disease-modifying therapy for a broad spectrum of fibrotic and scarring dermatologic disorders.
2026-06-19 | Late-Onset En Coup de Sabre: A Rare Presentation of Linear Scleroderma in an Elderly Woman.
En coup de sabre (ECDS) is a rare form of linear scleroderma that typically presents in childhood and may lead to progressive craniofacial tissue atrophy. Adult-onset disease is uncommon and may delay recognition. Early identification is important to prevent permanent deformity and potential neurologic complications. A 60-year-old woman with no significant past medical history presented with a nine-month history of progressive hyperpigmentation, skin tightening, and indentation involving the nasal bridge and left frontoparietal region. Over time, the discoloration extended toward the right forehead and was associated with contour changes of the nasal bridge and left forehead. Laboratory evaluation revealed a positive anti-histone antibody, with no evidence of systemic autoimmune or infectious disease. Imaging and endoscopic evaluation excluded sinonasal, bony, and intracranial pathology. Skin biopsy findings were consistent with a localized sclerosing process. A diagnosis of linear scleroderma ECDS was established. The patient was initiated on systemic corticosteroid therapy along with topical treatment and referred for multidisciplinary management. This case highlights an atypical late-onset presentation of ECDS. Although most cases occur in pediatric populations, adult-onset disease can present diagnostic challenges and may be associated with delayed recognition. The potential for neurologic involvement, even in the absence of initial symptoms, underscores the importance of careful evaluation and monitoring. Linear scleroderma ECDS should be considered in adults presenting with progressive craniofacial atrophy. Early diagnosis, prompt initiation of therapy, and ongoing neurologic surveillance are essential to reduce the risk of long-term functional and cosmetic sequelae.
2026-06-04 | Correlation of TTLL7-IT1/Hsa-miR-29c-3p/GLS with limited cutaneous systemic sclerosis and exploration of the underlying mechanisms.
Systemic sclerosis (SSc) is an autoimmune disease. In the types of SSc, lcSSc presents with milder symptoms and poses challenges for early diagnosis. Therefore, the identification of biomarkers for earlier diagnosis and the discovery of potential therapeutic targets are of greater significance. This study aims to explore the relationship between competing endogenous RNA (ceRNA) networks, cuproptosis, and lcSSc. RNA sequencing was performed to profile differentially expressed RNAs in blood samples from lcSSc patients and healthy controls. The potential ceRNA network targeting relationships were then examined using a dual-luciferase reporter assay. Subsequently, a series of in vitro experiments utilizing primary CD8+ T cells. These experiments, which included phenotypic assays and molecular analyses, demonstrated the occurrence of cuproptosis. Finally, these findings were validated in vivo in a mouse model through analyses of skin tissues using H&E staining, Masson staining, Immunofluorescence, qPCR, and Western blotting. TTLL7-IT1/hsa-miR-29c-3p/GLS was constructed using bioinformatic analysis of lcSSc. CD8+ T cells from patients with lcSSc exhibited elevated copper ion levels and reduced glutaminase(GLS) expression, accompanied by alterations in their phenotype and cuproptosis-related proteins. These phenotypic and protein expression changes were reversed by cuproptosis inhibition. Furthermore, cuproptosis exacerbates fibrosis and vascular pathology. Animal experiments further revealed that in bleomycin-induced mouse models, both inhibition of copper ions and GLS overexpression reduced dermal thickness, collagen deposition, fibrotic factor expression, and CD31/α-SMA co-localization in the skin. In summary, our findings reveal a functional interaction between cuproptosis and ceRNA networks: TTLL7-IT1/hsa-miR-29c-3p/GLS influences cuproptosis and lcSSc progression, providing new insights into the pathogenesis of lcSSc.
2026-06-01 | P148 Clinical profile and treatment outcomes in en coup de sabre: experience from a tertiary centre
Abstract En coup de sabre (ECDS) is a rare variant of linear localized scleroderma characterized by a linear, indurated and atrophic lesion involving the frontoparietal scalp and face. ECDS may be associated with neurological, ophthalmological and craniofacial involvement, contributing to significant morbidity. Early diagnosis and systemic immunosuppression are crucial to prevent disease progression and permanent sequelae. The aim of this study was to retrospectively evaluate the clinicodemographic profiles and treatment outcomes of patients with ECDS managed at a tertiary care centre. This retrospective study included 10 patients diagnosed with ECDS and registered between January 2023 and December 2024. Data extracted from medical records included clinicodemographic details; sites of involvement; laboratory investigations including antinuclear antibody (ANA) and brain magnetic resonance imaging (MRI) findings; treatment details and follow-up outcomes. All patients were treated with oral corticosteroids for 6 months along with weekly methotrexate for a duration of 1–1.5 years. The mean age of patients was 18.4 years (range 8–30), with a female-to-male ratio of 6 : 4. Age at disease onset ranged from 3 to 21 years, while disease duration at presentation varied from 0.5 to 19 years. Scalp and nasal involvement was observed in eight and five patients, respectively, and all patients had scalp and eyebrow alopecia. ANAs were negative in all cases. Brain MRI abnormalities were detected in seven patients. Three patients were lost to follow-up. Among the remaining patients, disease control was achieved within 1–2 months of treatment initiation, and sustained remission was observed at follow-up ranging from 1 to 3 years from baseline. ECDS demonstrates a heterogeneous clinical spectrum with frequent neurological involvement. Systemic therapy with oral corticosteroids and methotrexate was effective in achieving rapid disease control and sustained remission. Early diagnosis, routine neuroimaging and long-term follow-up are essential for optimal management of this rare condition.
proteins
2026-08-05 | Co-Occurrence of En Coup de Sabre, Parry-Romberg Syndrome, and Hemimasticatory Spasm: A Case Report.
En coup de sabre (ECDS) and Parry-Romberg syndrome (PRS) are rare, localised scleroderma subtypes, often considered to be overlapping variants of morphea. Hemimasticatory spasm (HMS), a distinct rare neuromuscular disorder characterised by unilateral paroxysmal contraction of the jaw muscles, has rarely been reported in association with these conditions. A 20-year-old man presented with a linear, cicatricial alopecic patch over the left parietal scalp, along with indurated and bound-down skin over the left cheek. This was followed by progressive depression and asymmetry of the left midface, accompanied by paroxysmal spasms during mastication and swallowing. Examination revealed cicatricial alopecia over the left parietal region and an atrophic plaque over the ipsilateral cheek. The left lower lip and tongue were atrophic, while the ipsilateral masseter muscle was visibly hypertrophied. Histopathological findings of the cheek lesion were consistent with morphea. A clinical diagnosis of co-existing ECDS, PRS, and HMS was made. Botulinum toxin type A was used to treat HMS, with marked reduction in symptoms and improvement in quality of life. This case highlights the rare but meaningful association between ECDS, PRS, and HMS, underscoring the importance of early recognition and multidisciplinary intervention. Botulinum toxin remains a valuable therapeutic option for managing symptomatic HMS in such contexts.
2026-07-08 | CCN3-derived peptide BLR-200 impairs YAP activation and attenuates bleomycin-induced skin fibrosis through blocking the generation of Sfrp2-positive fibroblasts
ABSTRACT An autocrine pro-adhesive/pro-contractile signaling loop, through the mechanosensitive transcriptional cofactor YAP, promotes fibrosis. The CCN family of matricellular proteins modify adhesive signaling. Of these, CCN3 is antifibrotic. We show that BLR-200, a CCN3-derived peptide, has anti-fibrotic properties in the bleomycin-induced model of scleroderma skin fibrosis. In vitro, BLR-200 delayed, but did not abolish, fibroblast adhesion to collagen and nuclear YAP localization. In vivo , BLR-200 prevented/treated bleomycin-induced skin fibrosis, and reduced bleomycin-induced expression of profibrotic genes including α-smooth muscle actin, CCN1 and CCN2. Lineage tracing and scRNA-seq analyses revealed that the myofibroblasts in this model were quantitatively derived from collagen-lineage Pi16+/Col15+ve fibroblasts. BLR-200 prevented myofibroblast differentiation in this model and trajectory of fibroblasts toward a Sfrp2-positive subset, a cell type associated with poor clinical outcome. BLR-200 impairs YAP activation in vitro and appearance of translationally-relevant fibroblast subtypes in vivo and is a novel anti-fibrotic agent for SSc skin fibrosis. HIGHLIGHTS -SSc skin fibrosis, a major unmet need, is driven by an activated mechanotransduction/YAP pathway; how to block this pathway clinically is unclear -members of the CCN family of matricellular proteins are adhesive signaling modifiers; herein, we identify BLR-200, a synthetic peptide derived from CCN3, based on its ability to impair, but not ablate, YAP nuclear localization and fibroblast spreading/attachment to collagen -BLR-200 blocks and treats progression of bleomycin-induced skin fibrosis -In the bleomycin model, lineage tracing analysis revealed that collagen-lineage cells are the primary source of myofibroblasts -BLR-200 blocks myofibroblast differentiation concomitant with reduced progression toward Col8a1+ve and Sfrp2+ ve fibroblasts, populations implicated in SSc pathogenesis -BLR-200 represents a novel, translationally relevant drug candidate for SSc skin fibrosis
2026-04-20 | Morphea En Coup De Sabre Treated With Combination Hyaluronic Acid Filler and Neuromodulator: A Case Report.
Morphea en coup de sabre is a localized scleroderma variant that often leaves permanent, disfiguring frontoparietal atrophy after disease stabilization. We report a 27-year-old woman with four stable, linear, atrophic forehead plaques consistent with burned-out morphea en coup de sabre who sought cosmetic improvement. Targeted prabotulinumtoxin-A was administered to hyperfunctional temporalis, corrugator supercilii, and depressor supercilii muscles to reduce dynamic deforming forces. Two weeks later, hyaluronic acid filler was delivered via a blunt-tipped microcannula on the periosteal plane in a zonal pattern to restore contour. This combination approach provided immediate, natural-appearing correction maintained with small-volume retreatments every six to 12 months without complications. This case illustrates that neuromodulator and hyaluronic acid filler, delivered with a cannula, may offer a safe, minimally invasive option for aesthetic rehabilitation of burned-out morphea en coup de sabre by addressing muscle imbalance while reshaping and contouring the forehead.
2026-03-11 | Human MAGI1 expression in endothelial cells protects from the development of localized and systemic scleroderma in mice
Abstract Background Systemic sclerosis and localized scleroderma are rheumatoid fibrotic diseases characterized by altered blood vessel permeability and dysregulated angiogenesis. MAGI1 is an intracellular protein expressed at the epithelial and endothelial cell junction, regulating cell adhesion and epithelial/endothelial integrity. Endothelial cell MAGI1 regulates angiogenic function and blood flow. In the present study, we investigated the role of transgenic human MAGI1 in endothelial cells in animal models of localized scleroderma and systemic sclerosis. Methods Wild-type and human MAGI1-overexpressing endothelial cells in mice were challenged with sodium hypochlorite or bleomycin injections to induce sclerosis/scleroderma, mimicking the human disease. Conventional methods and automated software were employed to investigate the integrity of lung and skin tissue and quantify fibrosis. In vivo permeability and in vitro angiogenic models were employed to investigate the regulation of endothelial cell function. Results Dermal thickening, lung tissue density, fibrotic foci development, and collagen accumulation induced by Bleomycin or sodium hypochlorite were significantly reduced in mice overexpressing human MAGI1 in endothelial cells relative to wild-type mice. Skin permeability and in vitro endothelial cell permeability were also reduced under MAGI1 overexpression. Furthermore, MAGI1 overexpression reduced the in vitro proangiogenic effects of VEGF-A, providing a putative mechanism of action. Conclusions The results indicate that endothelial cells expressing transgenic human MAGI1 attenuate tissue permeability and fibrotic responses in models of bleomycin- and sodium hypochlorite-induced scleroderma/sclerosis. MAGI1 overexpression blocks VEGF-A-induced permeability and angiogenesis in endothelial cells. Therefore, restoring endothelial cells could potentially alleviate VEGF-A-driven diseases such as localized scleroderma and systemic sclerosis.
2026-03-03 | Injectable platelet-rich fibrin as a valid therapeutic option for inactive linear morphea (en coup de saber): report of cases.
Localized scleroderma, also called morphea, is an inflammatory cutaneous disorder characterized by sclerosis of the skin and underlying tissues. Morphea is currently classified into 4 subtypes: limited, generalized, linear and mixed. Linear morphea in an en coup de saber pattern (LScs) manifests as band-like, atrophic lesions predominantly affecting the frontoparietal area, leading to facial contour defects and skin pigmentation. However, pharmacological treatments for LScs are limited in meeting the aesthetic expectations of patients. Recently, autologous platelet concentrates have shown great therapeutic potential for tissue regeneration and wound healing, while few studies have been conducted on their use in LScs patients. We present the first report of two patients with inactive LScs that were improved by treatment with injectable platelet-rich fibrin (i-PRF), a second-generation autologous platelet concentrate. Satisfactory aesthetic outcomes were both achieved in two patients within 5 injection sessions, with only mild pain and transient erythema after injection. Injectable platelet-rich fibrin can be a novel, valid therapeutic alternative for morphea management.
antibodies
2026-07-16 | IL-17 Signaling Inhibitors in Localized Scleroderma: A Single-Center Case Series of Nine Patients.
Localized scleroderma (LSc) is an autoimmune fibrosing disorder characterized by inflammation and sclerosis of the skin and underlying soft tissues. IL-17 signaling has been implicated in active inflammatory lesions, but treatment options for severe or refractory LSc remain limited. Here, we present nine patients with LSc treated with IL-17A or IL-17 receptor A inhibitors at our institution (ixekizumab, secukinumab, or brodalumab). These biologics were administered to patients refractory to conventional therapies or anticipated to have treatment-resistant disease, following institutional approval for unapproved drug use. Five patients improved, two stabilized, and two progressed. One patient developed pustulotic arthro-osteitis during brodalumab treatment, possibly representing a paradoxical reaction; no other major adverse events were observed. Although these uncontrolled retrospective data do not establish efficacy, they suggest that IL-17 pathway inhibition merits further study in selected patients with refractory LSc.
2026-07-03 | Spatial Orchestration of Skin Fibrosis by a CD8+ T cell-Myofibroblast Axis.
Fibrosing skin diseases are highly morbid conditions with diverse clinical and histopathologic features. Prior work, primarily in systemic sclerosis (SSc), has yielded mixed data regarding the immune drivers of fibrosis, as well as the identity and spatial localization of pro-fibrotic fibroblast cell subsets. Here, we focus on morphea and eosinophilic fasciitis (EF), which cause more acutely inflammatory skin fibrosis. Using multimodal single-nucleus and spatial transcriptomics, we find that effector CD8+ T cells are highly enriched in fibrotic skin. These cells are particularly abundant in inflammatory tissue domains bordering fibrotic stroma, which are marked by expression of interferon-γ stimulated genes. Inflammatory domains feature a loss of local homeostatic fibroblast populations and replacement with ADAM12-expressing inflammatory fibroblasts and myofibroblasts, which co-localize closely with CD8+ T cells. All subtypes of morphea featured similar patterns of CD8+ T-cell-associated fibro-inflammatory zonation and fibroblast transformation, suggesting that shared mechanisms can drive fibrosis across stromal compartments of skin. We apply these findings to a large publicly available scleroderma dataset and find that similar processes occur in SSc. Mechanistically, ablation of CD8+ T cells in mice ameliorates bleomycin-driven inflammation and fibrosis, as does fibroblast-intrinsic abrogation of IFN-γ signaling. These data establish CD8+ T cell-driven fibrogenesis as a key feature of fibrosing skin diseases and raise the prospect of targeting CD8+ T cells in autoimmune fibrosis more broadly. Spatial profiling of morphea-spectrum diseases reveals CD8 T cells as key drivers of fibrosis through fibroblast IFN-γ signaling.
2026-04-14 | Supplementary Table. Detailed Demographic and Clinical Characteristics of the Patients with Juvenile Localized Scleroderma
Plus signs (+) indicate positivity; “Negative” indicates negative results for ANA, RF, and the extended myositis/scleroderma panel.Abbreviations: F, female; M, male; y, years; m, months; mo, months; wk, weeks; Teli, telitacicept; ANA, antinuclear antibody; RF, rheumatoid factor; Anti-β2GP1, anti-beta-2 glycoprotein 1; Anti-PM-Scl, anti-polymyositis/scleroderma; MTX, methotrexate; Pred, prednisone.* Disease duration refers to the time from disease onset to the initiation of telitacicept. † Initial mLoSSI/LoSDI represent the clinical activity and damage scores assessed prior to the initiation of any first-line systemic therapy (MTX with or without Prednisone). ‡ Concomitant therapy refers to background medications maintained during telitacicept treatment. Standard dosages used in this study: MTX, 10-15 mg/m² once weekly (oral); Prednisone, 1 mg/kg/day (oral). § Prednisone taper duration indicates the time taken to successfully discontinue oral corticosteroids after starting telitacicept.“—” indicates no prednisone was used during the study period; “Still on” indicates the patient is currently tapering.
2026-02-27 | Successful tocilizumab-based combination therapy for a case of rapidly progressive adult deep morphea with multiple antiphospholipid antibodies: a case report and literature review.
Localized Scleroderma (LoS), particularly aggressive subtypes such as Deep Morphea (morphea profunda), is a rare chronic autoimmune fibrosing disorder that can extend into the subcutaneous tissue, fascia, and muscle. These deep forms carry a high risk of functional impairment. Tocilizumab (TCZ), an anti-interleukin-6 (IL-6) receptor antibody, has emerged as a promising therapy for severe, refractory cases. However, its reported use typically follows the failure of standard immunosuppressive agents like methotrexate (MTX). We report the case of a 19-year-old male with a rapidly progressive deep morphea of the left lower extremity, with only a two-month history from onset. Initial symptoms included skin hardening, hyperpigmentation, and mild restriction of foot motion. Skin biopsy confirmed deep morphea, showing lymphoplasmacytic inflammation and eosinophilic fibrosis extending into the subcutaneous septa and muscle interstitium. Pre-treatment magnetic resonance imaging (MRI) revealed prominent edema (high T2 signal) in the subcutaneous fat and blurred muscle fascial planes, consistent with active deep inflammation. Uniquely, the patient was seropositive for multiple antiphospholipid antibodies (aPLs), including Lupus Anticoagulant (dRVVT ratio 1.34), anti-phosphatidylserine/prothrombin IgM (143.72 U), β2-glycoprotein I IgM (30.9 CU), and anticardiolipin IgM (28.2 CU). Given the rapid progression and deep tissue involvement, an early intensified combination regimen of TCZ (640 mg IV every 4 weeks), MTX (12.5 mg weekly), high-dose corticosteroids (IV pulses followed by 30 mg/day oral prednisone taper), and prophylactic aspirin (100 mg daily) was initiated. Follow-up MRI at six months showed a marked reduction in the deep tissue edema, correlating with significant clinical improvement in skin induration and tightening by nine months post-treatment. No serious adverse events were observed during follow-up. This case demonstrates the successful outcome of early TCZ-based combination therapy in rapidly controlling the aggressive inflammatory process of an adult deep morphea. The objective radiological response validates this early intervention strategy, which deviates from the typical second-line use of TCZ. Furthermore, the case highlights a rare but clinically important overlap between severe localized scleroderma and multiple aPL seropositivity.
2026-01-01 | Supplemental Figure: Longitudinal Assessment of Disease Activity and Damage Scores During Telitacicept Therapy in Pediatric Refractory JLS
This figure illustrates the individual clinical trajectories for the seven pediatric patients with refractory juvenile localized scleroderma (JLS) treated with telitacicept。The x-axis represents the duration of telitacicept treatment in weeks, and the y-axis represents the validated clinical scores。Red circles (●) and lines indicate the modified Localized Scleroderma Skin Severity Index (mLoSSI), representing active inflammation including erythema, skin thickness, and new lesion extension。Blue squares (■) and lines indicate the Localized Scleroderma Skin Damage Index (LoSDI), representing accumulated tissue damage such as atrophy, subcutaneous fat loss, and pigmentation changes。A consistent decline in mLoSSI scores was observed in most patients, signifying the suppression of active disease, while LoSDI scores generally stabilized, even in patients with extended follow-up such as Patient 6, whose data now includes a 48-week evaluation to demonstrate the durability of the clinical response。Note that Patient 1 (Panel A) discontinued treatment after 24 weeks due to a lack of subjective improvement despite the reduction in activity scores, and Patient 7 (Panel G) had a follow-up duration of 12 weeks at the time of analysis.
cell therapies
2026-07-14 | Redistribution of Gaze Patterns in Facial Localized Scleroderma Following Autologous Fat Transfer: An Eye-Tracking Study.
The study aimed to use eye-tracking technology objectively quantifying changes in visual attention patterns in observers viewing faces of patients with facial localized scleroderma (LoS) before and after autologous fat transplantation (AFT). In this retrospective observational study, preoperative and postoperative standardized photographs of 30 patients with facial localized scleroderma (LoS) were presented to 50 observers. Gaze data were recorded using an eye tracker. Fixation proportions were analyzed for all affected regions and for specific facial subunits. A total of 30,266 fixation points were recorded. Postoperatively, the fixation proportion on the affected hemiface significantly decreased by 4.92% (p<0.05), with a concomitant increase in fixations redirected toward the unaffected side. Furthermore, an increase of 2.39% (p<0.05) in fixation proportion was observed in the central T-zone (periorbital and nasal regions). Subunit analysis revealed reductions in fixations on the affected cheek (16.12% to 10.39%, p<0.05) and forehead (17.18% to 13.23%, p<0.05). Stratified analysis showed that severe dermal atrophy and severe dyspigmentation were associated with less postoperative fixation reduction, whereas fixation reduction did not differ significantly by subcutaneous atrophy severity. AFT alters observers' visual attention by reducing fixations on the affected facial areas and redirecting gaze toward the unaffected side and the central T-zone. This shift suggests a partial redistribution of social-perceptual gaze patterns toward a more typical facial viewing pattern. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
2026-03-09 | A novel microneedle-based delivery of NRF2-overexpressing exosomes for scleroderma therapy.
Scleroderma is a chronic autoimmune connective tissue disease characterized by progressive skin fibrosis, vascular dysfunction, and immune dysregulation. Current therapies remain largely ineffective in reversing established fibrosis and are limited by systemic side effects. In this study, we developed a novel therapeutic strategy combining microneedle (MN)-mediated transdermal delivery with NRF2-overexpressing exosomes (NRF2-OE Exos) to locally enhance antioxidant, anti-fibrotic, anti-inflammatory, and pro-angiogenic effects in scleroderma. Exosomes were isolated from NRF2-OE adipose-derived stem cells (ADSCs) and incorporated into GelMA/PEGDA-based dissolvable MNs. These MNs demonstrated excellent mechanical strength, minimal invasiveness, sustained exosome release, and efficient cellular uptake in vitro. Functional assays showed that NRF2-OE Exos-loaded MNs significantly enhanced endothelial tube formation, preserved fibroblast mitochondrial integrity, and promoted macrophage polarization toward a reparative phenotype. In a bleomycin-induced murine scleroderma model, MN treatment reduced dermal thickening, collagen deposition, and α-SMA expression while promoting vascular regeneration and immunomodulation. Mechanistically, transcriptomic analysis revealed that NRF2-OE Exos suppressed pro-fibrotic Wnt and Hippo signaling pathways and activated calcium and cAMP signaling pathways. Moreover, NRF2-OE Exos alleviated mitochondrial dysfunction and ferroptotic injury by upregulating antioxidant and lipid peroxidation defense genes. Collectively, this study demonstrates that MN-mediated delivery of engineered exosomes offers a promising, localized, and multifaceted therapeutic approach for scleroderma, with strong translational potential.
2026-01-01 | Fat Grafting and Dermal Fat Grafting for Localized Scleroderma of the Forehead: A Colorimetric Analysis of Surgical Outcomes
Objectives: Localized scleroderma (LS) is characterized by skin fibrosis and dyschromia. Fat grafting and dermal fat grafting are surgical options used to improve these features. In this study, we aimed to objectively compare postoperative color improvement between the two techniques using the CIEDE2000 (ΔE00) color difference formula.
2025-09-26 | Exploring the Therapeutic Potential of Adipose-Derived Stem Cells in Attenuating Skin Fibrosis: Insights from a Bleomycin-Induced Murine Model
BACKGROUND: Scleroderma, characterized by excessive collagen deposition and dysregulated immune responses, leads to debilitating skin fibrosis. Adipose-derived stem cells (ADSCs) exhibit antifibrotic and immunomodulatory properties, but their dynamic interactions within fibrotic microenvironments remain underexplored. This study investigates the temporal effects of ADSCs on skin fibrosis and elucidates their molecular mechanisms. METHODS: A bleomycin (BLM)-induced skin fibrosis model was established in C57BL/6J mice. GFP-labeled ADSCs were subcutaneously injected into fibrotic lesions, with follow-up analyses at days 1, 7, 14, and 21 post-injection. Histopathological evaluation (H&E, Masson’s trichrome, α-SMA staining), qRT-PCR, flow cytometry, and RNA sequencing were performed to assess fibrosis progression, inflammatory cytokine levels, and ADSC behavior. In vitro co-culture experiments with human scleroderma-derived fibroblasts validated key pathways. RESULTS: ADSCs localized preferentially to hair follicles and perivascular regions, with survival declining by day 21. BLM-induced dermal thickening, collagen disorganization, and α-SMA expression were significantly reduced by ADSC treatment (p<0.05). Proinflammatory cytokines (TNF-α, IL-6, IL-1β) surged post-BLM induction but decreased sharply after ADSC administration. RNA sequencing revealed time-dependent transcriptomic shifts: immunomodulatory pathways (e.g., IL-6 production, VEGF signaling) dominated at day 7, while antifibrotic pathways (collagen matrix regulation, TGF-β/Smad inhibition) emerged by day 14. TSG-6, a critical antifibrotic mediator, was upregulated in ADSCs within fibrotic environments. Silencing TSG-6 in ADSCs abolished their antifibrotic effects, restoring COL1 and α-SMA expression in fibroblasts (p<0.05). In vivo, TSG-6-deficient ADSCs failed to suppress TGF-β/Smad2/3 activation, confirming its pivotal role. CONCLUSION: ADSCs exert dual-phase therapeutic effects: early immunomodulation (days 1–7) followed by sustained antifibrotic action (days 14–21), mediated partly via TSG-6-dependent TGF-β/Smad pathway inhibition. These findings highlight ADSCs as a promising cell-based therapy for fibrotic skin disorders, offering insights into optimizing timing and mechanisms for clinical translation.
2025-09-24 | Injectable Immune-Regulating Mesenchymal Stem Cells Hydrogel for Localized Scleroderma Treatment.
Bioactive hydrogels with anti-inflammatory, antioxidant, and pro-angiogenic properties are crucial for unlocking the full potential of mesenchymal stem cells (MSCs) therapy for scleroderma treatment. Here, drawing inspiration from the adhesion, antioxidant, and inflammation regulation ability of green tea, we introduce an injectable MSCs hydrogel containing immune-regulating polyphenol nanozymes to treat localized scleroderma. The hydrogel is constructed based on the dynamic Schiff reaction, which could endow it with injectability, self-healing function, and tissue adhesion. The introduction of natural polyphenol-based nanozymes can enhance the reactive oxygen species (ROS) scavenging and anti-inflammatory capabilities of the hydrogel and facilitate macrophage transformation. Besides, the hydrogel provides a conducive three-dimensional (3D) growth environment for MSCs in vitro, effectively promoting the ability of MSCs in the antifibrosis, vascular endothelial cells migration, and neovascularization. We have demonstrated that our hydrogel could accelerate the recovery of scleroderma lesions by inhibiting the expression of pro-inflammatory and fibrotic factors, promoting angiogenesis, remodeling skin appendages, and enhancing the expression of anti-inflammatory factors in a mouse scleroderma model. These results suggest that our injectable polyphenol nanozyme MSCs hydrogel presents a potential therapeutic strategy for managing scleroderma.
other
2025-04-25 | miR-143-3p boosts extracellular vesicles to improve the dermal fibrosis of localized scleroderma.
Localized scleroderma (LoSc) is an autoimmune disease that features extensive fibrosis of the skin. Due to its severity and limited understanding, no effective treatments have been developed to date. Bone marrow mesenchymal stem cells (BMSCs) derived extracellular vesicles (EVs) have been demonstrated promising therapeutic effects on the LoSc mouse model in our previous study. However, identifying the targets and underlying mechanisms of EVs remains a significant challenge for therapeutic applications. miR-143-3p, a critical and abundant factor in BMSC-EVs identified through miRNA sequencing, mediates antifibrotic effects in a LoSc mouse model and is significantly lacking in the dermis of LoSc patients. This microRNA inhibits myofibroblast formation and collagen synthesis, contributing to the therapeutic effects of BMSC-EVs in the LoSc mouse model. Moreover, miR-143-3p-reinforced BMSC-EVs demonstrated enhanced therapeutic efficacy compared to normal BMSC-EVs, reducing dermal thickening, collagen deposition, fibroblast differentiation into myofibroblasts, and promoting skin tissue remodeling. IGF1R, highly expressed in the skin of LoSc, was identified as a potential target of miR-143-3p and was inhibited by miR-143-3p-reinforced EVs, thereby modulating the IGF1/IGF1R-AKT/MAPK pathway. In conclusion, miR-143-3p-enriched EVs could be a more efficient candidate for treating dermal fibrosis in LoSc.
2024-11-22 | miR-3606-3p alleviates skin fibrosis by integratively suppressing the integrin/FAK, p-AKT/p-ERK, and TGF-β signaling cascades.
Fibroblast abnormalities are crucial causes of skin fibrosis, including systemic sclerosis (SSc) and keloids. However, their mechanisms, including underlying microRNA regulatory mechanisms, remain elusive. This study aimed to evaluate the roles, mechanisms, and therapeutic potential of miR-3606-3p in regulating multiple fibroblast abnormalities. The miR-3606-3p levels were evaluated in skin tissues and primary fibroblasts. RNA-seq and luciferase assays were employed to identify miR-3606-3p targets. Collagen contraction, western blotting, in vivo imaging, and real-time cellular analysis were used to assess fibroblast abnormalities. The therapeutic potential of miR-3606-3p was evaluated in mice. MiR-3606-3p decreased in skin tissues (SSc: Fold Change (FC) = - 2.95, P = 0.0101; keloid: FC = - 3.42, P < 0.0001) and primary fibroblasts (SSc: FC = - 12.74, P = 0.0278; keloid: FC = - 2.08, P = 0.0021) from skin fibrosis patients, and negatively correlated with disease severity. Mechanistically, miR-3606-3p targeted the 3'-untranslated regions (3'-UTRs) of Integrin αV (ITGAV), GRB2-associated binding protein 1 (GAB1), and transforming growth factor beta receptor 2 (TGFBR2), all of these three targets increased in skin fibrosis. Simultaneously, miR-3606-3p inhibited fibroblast's fibrogenesis, migration, inflammation, and proliferation by inhibiting ITGAV/integrin/FAK, GAB1/p-AKT/p-ERK, and TGFBR2/p-SMAD2/3 signaling. ITGAV-mediated integrin/FAK signaling unidirectionally activated the p-AKT/p-ERK and p-SMAD2/3 pathways. Knockdown of GAB1 and TGFRB2 reduced ITGAV-induced p-AKT/p-ERK and p-SMAD2/3 activities. MiR-3606-3p, si-ITGAV, si-GAB1, and si-TGFBR2 exhibited significant inhibition of fibrogenesis and migration. Inflammation was primarily inhibited by si-ITGAV and si-GAB1, while proliferation was primarily inhibited by si-TGFBR2. Moreover, miR-3606-3p significantly attenuates skin fibrosis in keloid-bearing mice. MiR-3606-3p is downregulated in skin fibrosis. Moreover, it negatively correlates with disease severity. Functionally, miR-3606-3p inhibits fibrogenesis, migration, inflammation, and proliferation of fibroblasts. Mechanistically, miR-3606-3p inhibits ITGAV, GAB1, and TGFBR2 by targeting their 3'-UTRs. ITGAV-, GAB1-, and TGFBR2-activated integrin/AKT/ERK/SMAD2/3 signaling induced fibroblast abnormalities. In vivo, miR-3606-3p inhibits skin fibrosis in mice. Therefore, the multi-targeting, multi-phenotypic regulatory properties of miR-3606-3p suggest its potential utility in clinical treatment.
2022-12-27 | Identification of lncRNA expression profiles in pediatric localized scleroderma.
The role and potential molecular mechanism of inflammatory cells in pediatric localized scleroderma are poorly investigated. In this study, we first investigated the profiling of inflammatory cells in skin samples from pediatric localized scleroderma. Among them, CD4+ T-cells were up-regulated. Co-culture dermal fibroblasts with CD4+ T-cells promoted fibrosis of fibroblasts. Candidate lncRNAs were further explored by lncRNAs-seq between the normal skin tissues and pediatric localized scleroderma tissues, and the lncRNAs-seq between fibroblasts co-cultured with CD4+ T lymphocytes and control fibroblasts. By comparing the two datasets, we identified eight up-regulated and three down-regulated lncRNAs, which were the potential lncRNAs for the phenotype of pediatric localized scleroderma. Here, we identified the CD4+ T-cells infiltration in pediatric localized scleroderma and potential lncRNAs for the treatment of pediatric localized scleroderma.
2022-06-27 | Elevated Alpha 1(I) to Alpha 2(I) Collagen Ratio in Dermal Fibroblasts Possibly Contributes to Fibrosis in Systemic Sclerosis.
Systemic sclerosis (SSc) is characterized by excessive collagen deposition in the skin and internal organs. Activated fibroblasts are the key effector cells for the overproduction of type I collagen, which comprises the α1(I) and α2(I) chains encoded by COL1A1 and COL1A2, respectively. In this study, we examined the expression patterns of α1(I) and α2(I) collagen in SSc fibroblasts, as well as their co-regulation with each other. The relative expression ratio of COL1A1 to COL1A2 in SSc fibroblasts was significantly higher than that in control fibroblasts. The same result was observed for type I collagen protein levels, indicating that α2(I) collagen is more elevated than α2(I) collagen. Inhibition or overexpression of α1(I) collagen in control fibroblasts affected the α2(I) collagen levels, suggesting that α1(I) collagen might act as an upstream regulator of α2(I) collagen. The local injection of COL1A1 small interfering RNA in a bleomycin-induced SSc mouse model was found to attenuate skin fibrosis. Overall, our data indicate that α2(I) collagen is a potent regulator of type I collagen in SSc; further investigations of the overall regulatory mechanisms of type I collagen may help understand the aberrant collagen metabolism in SSc.
2018-11-01 | Progranulin overproduction due to constitutively activated c-Abl/PKC-δ/Fli1 pathway contributes to the resistance of dermal fibroblasts to the anti-fibrotic effect of tumor necrosis factor-α in localized scleroderma
Dermal fibroblasts derived from patients with systemic sclerosis (SSc) overproduce progranulin (PGRN), an endogenous antagonist of tumor necrosis factor (TNF) receptors, due to the deficiency of transcription factor Fli1. Fli1 expression is also decreased in dermal fibroblasts derived from patients with localized scleroderma (LSc).To investigate the expression levels of PGRN and its contribution to the induction of pro-fibrotic phenotype in LSc dermal fibroblasts.PGRN expression levels were determined by immunohistochemistry and quantitative reverse transcription PCR in the skin of human subjects. The role of PGRN in fibroblast activation was examined with gene silencing technique. The involvement of c-Abl/protein kinase C (PKC)-δ/Fli1 pathway in the regulation of PGRN expression was investigated by immunoblotting.The expression levels of PGRN and TNF-α were elevated in LSc skin lesions compared with healthy control skin. LSc dermal fibroblasts were less responsive to the anti-fibrotic effect of TNF-α than normal dermal fibroblasts. Importantly, gene silencing of PGRN reversed the response to TNF-α in LSc dermal fibroblasts. Similar to SSc dermal fibroblasts, the inhibition of c-Abl/PKC-δ/Fli1 pathway by gene silencing of ABL1 or PRKCD significantly suppressed PGRN expression in LSc dermal fibroblasts.PGRN overproduction due to constitutively activated c-Abl/PKC-δ/Fli1 pathway may contribute to the resistance of LSc dermal fibroblasts to the anti-fibrotic effect of TNF-α, which may be involved in maintaining their pro-fibrotic phenotype under the pro-inflammatory condition, as is the case with SSc.
small molecules
2026-07-28 | Spatially resolved gene programs and cell neighborhoods of scleroderma fibroblasts 2261024
Abstract Introduction Systemic sclerosis (SSc, scleroderma) is a chronic autoimmune disease with high mortality, characterized by progressive fibrosis of the skin and internal organs. Skin involvement is among the earliest manifestations of disease, and changes in skin pathology can mirror systemic progression. While single-cell studies have revealed striking transcriptional diversity among dermal fibroblasts in SSc, the spatial organization and immune signals that govern their function remain unclear. Methods To address this, we performed high-resolution spatial transcriptomic profiling of clinically affected and unaffected skin from SSc donors alongside healthy controls. Results We identify known disease-associated fibroblast subsets, including COMP+ myofibroblasts, which localize within cell neighborhoods enriched in activated endothelial and immune cells. In contrast, LGR5+/PI16+ fibroblasts — abundant in healthy skin and previously shown to contain a T cell-inducible gene program — are significantly reduced in both clinically involved and uninvolved SSc skin and occupy distinct microenvironments from disease-associated cells. Conclusion Our findings provide a spatial framework for understanding fibroblast heterogeneity and identify potential therapeutic strategies aimed at reinforcing protective fibroblast programs to prevent or delay fibrosis in scleroderma. Funding Source R21AI185642 NIAID/NIH, National Scleroderma Foundation Topic Categories Immune Mechanisms of Human Disease (HUM)
2026-06-22 | Pioglitazone in Skin Fibrosis: Mechanistic Rationale and Therapeutic Potential of Pioglitazone for Scarring Dermatoses.
Cutaneous fibrosis - encompassing keloids, hypertrophic scars, localized scleroderma (morphea), and scarring alopecias - remains fundamentally undertreated, with conventional interventions frequently yielding incomplete therapeutic responses and high rates of recurrence. Pioglitazone, a Food and Drug Administration (FDA)-approved peroxisome proliferator-activated receptor γ (PPAR-γ) agonist traditionally utilized for glycemic control in type 2 diabetes mellitus, represents a highly compelling candidate for dermatologic repurposing. Beyond its canonical metabolic functions, robust target engagement of PPAR-γ by pioglitazone suppresses NF-κB-driven cytokine cascades, directly inhibits NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome assembly, promotes macrophage polarization toward tissue-reparative phenotypes, and disrupts profibrotic TGF-β/SMAD signaling architectures. Consequently, the drug exerts a dual mechanism of action, simultaneously attenuating chronic inflammation while inhibiting pathological fibrogenesis. This review expands upon prior analyses by integrating recently published clinical and scientific data, specifically highlighting new translational milestones, including human registry data in progeroid syndromes and randomized controlled trials in cicatricial alopecia. A distinct focus is placed on advancements in localized delivery strategies, such as nanostructured lipid carriers and niosomes, that offer the potential to overcome pioglitazone's inherent physicochemical constraints and thereby maximize dermal target engagement while avoiding systemic toxicities like heart failure and bladder cancer. Furthermore, this analysis synthesizes recent molecular insights connecting fibrosis and inflammation via target engagement biomarkers (e.g., FABP4, CD36) and proposes actionable, biomarker-driven trial designs, including adaptive basket trials, to bridge current gaps in dermatology-specific translation. Demonstrating localized anti-fibrotic and anti-inflammatory efficacy with minimal systemic risk could establish pioglitazone as a mechanism-based, disease-modifying therapy for a broad spectrum of fibrotic and scarring dermatologic disorders.
2026-06-19 | Late-Onset En Coup de Sabre: A Rare Presentation of Linear Scleroderma in an Elderly Woman.
En coup de sabre (ECDS) is a rare form of linear scleroderma that typically presents in childhood and may lead to progressive craniofacial tissue atrophy. Adult-onset disease is uncommon and may delay recognition. Early identification is important to prevent permanent deformity and potential neurologic complications. A 60-year-old woman with no significant past medical history presented with a nine-month history of progressive hyperpigmentation, skin tightening, and indentation involving the nasal bridge and left frontoparietal region. Over time, the discoloration extended toward the right forehead and was associated with contour changes of the nasal bridge and left forehead. Laboratory evaluation revealed a positive anti-histone antibody, with no evidence of systemic autoimmune or infectious disease. Imaging and endoscopic evaluation excluded sinonasal, bony, and intracranial pathology. Skin biopsy findings were consistent with a localized sclerosing process. A diagnosis of linear scleroderma ECDS was established. The patient was initiated on systemic corticosteroid therapy along with topical treatment and referred for multidisciplinary management. This case highlights an atypical late-onset presentation of ECDS. Although most cases occur in pediatric populations, adult-onset disease can present diagnostic challenges and may be associated with delayed recognition. The potential for neurologic involvement, even in the absence of initial symptoms, underscores the importance of careful evaluation and monitoring. Linear scleroderma ECDS should be considered in adults presenting with progressive craniofacial atrophy. Early diagnosis, prompt initiation of therapy, and ongoing neurologic surveillance are essential to reduce the risk of long-term functional and cosmetic sequelae.
2026-06-04 | Correlation of TTLL7-IT1/Hsa-miR-29c-3p/GLS with limited cutaneous systemic sclerosis and exploration of the underlying mechanisms.
Systemic sclerosis (SSc) is an autoimmune disease. In the types of SSc, lcSSc presents with milder symptoms and poses challenges for early diagnosis. Therefore, the identification of biomarkers for earlier diagnosis and the discovery of potential therapeutic targets are of greater significance. This study aims to explore the relationship between competing endogenous RNA (ceRNA) networks, cuproptosis, and lcSSc. RNA sequencing was performed to profile differentially expressed RNAs in blood samples from lcSSc patients and healthy controls. The potential ceRNA network targeting relationships were then examined using a dual-luciferase reporter assay. Subsequently, a series of in vitro experiments utilizing primary CD8+ T cells. These experiments, which included phenotypic assays and molecular analyses, demonstrated the occurrence of cuproptosis. Finally, these findings were validated in vivo in a mouse model through analyses of skin tissues using H&E staining, Masson staining, Immunofluorescence, qPCR, and Western blotting. TTLL7-IT1/hsa-miR-29c-3p/GLS was constructed using bioinformatic analysis of lcSSc. CD8+ T cells from patients with lcSSc exhibited elevated copper ion levels and reduced glutaminase(GLS) expression, accompanied by alterations in their phenotype and cuproptosis-related proteins. These phenotypic and protein expression changes were reversed by cuproptosis inhibition. Furthermore, cuproptosis exacerbates fibrosis and vascular pathology. Animal experiments further revealed that in bleomycin-induced mouse models, both inhibition of copper ions and GLS overexpression reduced dermal thickness, collagen deposition, fibrotic factor expression, and CD31/α-SMA co-localization in the skin. In summary, our findings reveal a functional interaction between cuproptosis and ceRNA networks: TTLL7-IT1/hsa-miR-29c-3p/GLS influences cuproptosis and lcSSc progression, providing new insights into the pathogenesis of lcSSc.
2026-06-01 | P148 Clinical profile and treatment outcomes in en coup de sabre: experience from a tertiary centre
Abstract En coup de sabre (ECDS) is a rare variant of linear localized scleroderma characterized by a linear, indurated and atrophic lesion involving the frontoparietal scalp and face. ECDS may be associated with neurological, ophthalmological and craniofacial involvement, contributing to significant morbidity. Early diagnosis and systemic immunosuppression are crucial to prevent disease progression and permanent sequelae. The aim of this study was to retrospectively evaluate the clinicodemographic profiles and treatment outcomes of patients with ECDS managed at a tertiary care centre. This retrospective study included 10 patients diagnosed with ECDS and registered between January 2023 and December 2024. Data extracted from medical records included clinicodemographic details; sites of involvement; laboratory investigations including antinuclear antibody (ANA) and brain magnetic resonance imaging (MRI) findings; treatment details and follow-up outcomes. All patients were treated with oral corticosteroids for 6 months along with weekly methotrexate for a duration of 1–1.5 years. The mean age of patients was 18.4 years (range 8–30), with a female-to-male ratio of 6 : 4. Age at disease onset ranged from 3 to 21 years, while disease duration at presentation varied from 0.5 to 19 years. Scalp and nasal involvement was observed in eight and five patients, respectively, and all patients had scalp and eyebrow alopecia. ANAs were negative in all cases. Brain MRI abnormalities were detected in seven patients. Three patients were lost to follow-up. Among the remaining patients, disease control was achieved within 1–2 months of treatment initiation, and sustained remission was observed at follow-up ranging from 1 to 3 years from baseline. ECDS demonstrates a heterogeneous clinical spectrum with frequent neurological involvement. Systemic therapy with oral corticosteroids and methotrexate was effective in achieving rapid disease control and sustained remission. Early diagnosis, routine neuroimaging and long-term follow-up are essential for optimal management of this rare condition.
proteins
2026-08-05 | Co-Occurrence of En Coup de Sabre, Parry-Romberg Syndrome, and Hemimasticatory Spasm: A Case Report.
En coup de sabre (ECDS) and Parry-Romberg syndrome (PRS) are rare, localised scleroderma subtypes, often considered to be overlapping variants of morphea. Hemimasticatory spasm (HMS), a distinct rare neuromuscular disorder characterised by unilateral paroxysmal contraction of the jaw muscles, has rarely been reported in association with these conditions. A 20-year-old man presented with a linear, cicatricial alopecic patch over the left parietal scalp, along with indurated and bound-down skin over the left cheek. This was followed by progressive depression and asymmetry of the left midface, accompanied by paroxysmal spasms during mastication and swallowing. Examination revealed cicatricial alopecia over the left parietal region and an atrophic plaque over the ipsilateral cheek. The left lower lip and tongue were atrophic, while the ipsilateral masseter muscle was visibly hypertrophied. Histopathological findings of the cheek lesion were consistent with morphea. A clinical diagnosis of co-existing ECDS, PRS, and HMS was made. Botulinum toxin type A was used to treat HMS, with marked reduction in symptoms and improvement in quality of life. This case highlights the rare but meaningful association between ECDS, PRS, and HMS, underscoring the importance of early recognition and multidisciplinary intervention. Botulinum toxin remains a valuable therapeutic option for managing symptomatic HMS in such contexts.
2026-07-08 | CCN3-derived peptide BLR-200 impairs YAP activation and attenuates bleomycin-induced skin fibrosis through blocking the generation of Sfrp2-positive fibroblasts
ABSTRACT An autocrine pro-adhesive/pro-contractile signaling loop, through the mechanosensitive transcriptional cofactor YAP, promotes fibrosis. The CCN family of matricellular proteins modify adhesive signaling. Of these, CCN3 is antifibrotic. We show that BLR-200, a CCN3-derived peptide, has anti-fibrotic properties in the bleomycin-induced model of scleroderma skin fibrosis. In vitro, BLR-200 delayed, but did not abolish, fibroblast adhesion to collagen and nuclear YAP localization. In vivo , BLR-200 prevented/treated bleomycin-induced skin fibrosis, and reduced bleomycin-induced expression of profibrotic genes including α-smooth muscle actin, CCN1 and CCN2. Lineage tracing and scRNA-seq analyses revealed that the myofibroblasts in this model were quantitatively derived from collagen-lineage Pi16+/Col15+ve fibroblasts. BLR-200 prevented myofibroblast differentiation in this model and trajectory of fibroblasts toward a Sfrp2-positive subset, a cell type associated with poor clinical outcome. BLR-200 impairs YAP activation in vitro and appearance of translationally-relevant fibroblast subtypes in vivo and is a novel anti-fibrotic agent for SSc skin fibrosis. HIGHLIGHTS -SSc skin fibrosis, a major unmet need, is driven by an activated mechanotransduction/YAP pathway; how to block this pathway clinically is unclear -members of the CCN family of matricellular proteins are adhesive signaling modifiers; herein, we identify BLR-200, a synthetic peptide derived from CCN3, based on its ability to impair, but not ablate, YAP nuclear localization and fibroblast spreading/attachment to collagen -BLR-200 blocks and treats progression of bleomycin-induced skin fibrosis -In the bleomycin model, lineage tracing analysis revealed that collagen-lineage cells are the primary source of myofibroblasts -BLR-200 blocks myofibroblast differentiation concomitant with reduced progression toward Col8a1+ve and Sfrp2+ ve fibroblasts, populations implicated in SSc pathogenesis -BLR-200 represents a novel, translationally relevant drug candidate for SSc skin fibrosis
2026-04-20 | Morphea En Coup De Sabre Treated With Combination Hyaluronic Acid Filler and Neuromodulator: A Case Report.
Morphea en coup de sabre is a localized scleroderma variant that often leaves permanent, disfiguring frontoparietal atrophy after disease stabilization. We report a 27-year-old woman with four stable, linear, atrophic forehead plaques consistent with burned-out morphea en coup de sabre who sought cosmetic improvement. Targeted prabotulinumtoxin-A was administered to hyperfunctional temporalis, corrugator supercilii, and depressor supercilii muscles to reduce dynamic deforming forces. Two weeks later, hyaluronic acid filler was delivered via a blunt-tipped microcannula on the periosteal plane in a zonal pattern to restore contour. This combination approach provided immediate, natural-appearing correction maintained with small-volume retreatments every six to 12 months without complications. This case illustrates that neuromodulator and hyaluronic acid filler, delivered with a cannula, may offer a safe, minimally invasive option for aesthetic rehabilitation of burned-out morphea en coup de sabre by addressing muscle imbalance while reshaping and contouring the forehead.
2026-03-11 | Human MAGI1 expression in endothelial cells protects from the development of localized and systemic scleroderma in mice
Abstract Background Systemic sclerosis and localized scleroderma are rheumatoid fibrotic diseases characterized by altered blood vessel permeability and dysregulated angiogenesis. MAGI1 is an intracellular protein expressed at the epithelial and endothelial cell junction, regulating cell adhesion and epithelial/endothelial integrity. Endothelial cell MAGI1 regulates angiogenic function and blood flow. In the present study, we investigated the role of transgenic human MAGI1 in endothelial cells in animal models of localized scleroderma and systemic sclerosis. Methods Wild-type and human MAGI1-overexpressing endothelial cells in mice were challenged with sodium hypochlorite or bleomycin injections to induce sclerosis/scleroderma, mimicking the human disease. Conventional methods and automated software were employed to investigate the integrity of lung and skin tissue and quantify fibrosis. In vivo permeability and in vitro angiogenic models were employed to investigate the regulation of endothelial cell function. Results Dermal thickening, lung tissue density, fibrotic foci development, and collagen accumulation induced by Bleomycin or sodium hypochlorite were significantly reduced in mice overexpressing human MAGI1 in endothelial cells relative to wild-type mice. Skin permeability and in vitro endothelial cell permeability were also reduced under MAGI1 overexpression. Furthermore, MAGI1 overexpression reduced the in vitro proangiogenic effects of VEGF-A, providing a putative mechanism of action. Conclusions The results indicate that endothelial cells expressing transgenic human MAGI1 attenuate tissue permeability and fibrotic responses in models of bleomycin- and sodium hypochlorite-induced scleroderma/sclerosis. MAGI1 overexpression blocks VEGF-A-induced permeability and angiogenesis in endothelial cells. Therefore, restoring endothelial cells could potentially alleviate VEGF-A-driven diseases such as localized scleroderma and systemic sclerosis.
2026-03-03 | Injectable platelet-rich fibrin as a valid therapeutic option for inactive linear morphea (en coup de saber): report of cases.
Localized scleroderma, also called morphea, is an inflammatory cutaneous disorder characterized by sclerosis of the skin and underlying tissues. Morphea is currently classified into 4 subtypes: limited, generalized, linear and mixed. Linear morphea in an en coup de saber pattern (LScs) manifests as band-like, atrophic lesions predominantly affecting the frontoparietal area, leading to facial contour defects and skin pigmentation. However, pharmacological treatments for LScs are limited in meeting the aesthetic expectations of patients. Recently, autologous platelet concentrates have shown great therapeutic potential for tissue regeneration and wound healing, while few studies have been conducted on their use in LScs patients. We present the first report of two patients with inactive LScs that were improved by treatment with injectable platelet-rich fibrin (i-PRF), a second-generation autologous platelet concentrate. Satisfactory aesthetic outcomes were both achieved in two patients within 5 injection sessions, with only mild pain and transient erythema after injection. Injectable platelet-rich fibrin can be a novel, valid therapeutic alternative for morphea management.
antibodies
2026-07-16 | IL-17 Signaling Inhibitors in Localized Scleroderma: A Single-Center Case Series of Nine Patients.
Localized scleroderma (LSc) is an autoimmune fibrosing disorder characterized by inflammation and sclerosis of the skin and underlying soft tissues. IL-17 signaling has been implicated in active inflammatory lesions, but treatment options for severe or refractory LSc remain limited. Here, we present nine patients with LSc treated with IL-17A or IL-17 receptor A inhibitors at our institution (ixekizumab, secukinumab, or brodalumab). These biologics were administered to patients refractory to conventional therapies or anticipated to have treatment-resistant disease, following institutional approval for unapproved drug use. Five patients improved, two stabilized, and two progressed. One patient developed pustulotic arthro-osteitis during brodalumab treatment, possibly representing a paradoxical reaction; no other major adverse events were observed. Although these uncontrolled retrospective data do not establish efficacy, they suggest that IL-17 pathway inhibition merits further study in selected patients with refractory LSc.
2026-07-03 | Spatial Orchestration of Skin Fibrosis by a CD8+ T cell-Myofibroblast Axis.
Fibrosing skin diseases are highly morbid conditions with diverse clinical and histopathologic features. Prior work, primarily in systemic sclerosis (SSc), has yielded mixed data regarding the immune drivers of fibrosis, as well as the identity and spatial localization of pro-fibrotic fibroblast cell subsets. Here, we focus on morphea and eosinophilic fasciitis (EF), which cause more acutely inflammatory skin fibrosis. Using multimodal single-nucleus and spatial transcriptomics, we find that effector CD8+ T cells are highly enriched in fibrotic skin. These cells are particularly abundant in inflammatory tissue domains bordering fibrotic stroma, which are marked by expression of interferon-γ stimulated genes. Inflammatory domains feature a loss of local homeostatic fibroblast populations and replacement with ADAM12-expressing inflammatory fibroblasts and myofibroblasts, which co-localize closely with CD8+ T cells. All subtypes of morphea featured similar patterns of CD8+ T-cell-associated fibro-inflammatory zonation and fibroblast transformation, suggesting that shared mechanisms can drive fibrosis across stromal compartments of skin. We apply these findings to a large publicly available scleroderma dataset and find that similar processes occur in SSc. Mechanistically, ablation of CD8+ T cells in mice ameliorates bleomycin-driven inflammation and fibrosis, as does fibroblast-intrinsic abrogation of IFN-γ signaling. These data establish CD8+ T cell-driven fibrogenesis as a key feature of fibrosing skin diseases and raise the prospect of targeting CD8+ T cells in autoimmune fibrosis more broadly. Spatial profiling of morphea-spectrum diseases reveals CD8 T cells as key drivers of fibrosis through fibroblast IFN-γ signaling.
2026-04-14 | Supplementary Table. Detailed Demographic and Clinical Characteristics of the Patients with Juvenile Localized Scleroderma
Plus signs (+) indicate positivity; “Negative” indicates negative results for ANA, RF, and the extended myositis/scleroderma panel.Abbreviations: F, female; M, male; y, years; m, months; mo, months; wk, weeks; Teli, telitacicept; ANA, antinuclear antibody; RF, rheumatoid factor; Anti-β2GP1, anti-beta-2 glycoprotein 1; Anti-PM-Scl, anti-polymyositis/scleroderma; MTX, methotrexate; Pred, prednisone.* Disease duration refers to the time from disease onset to the initiation of telitacicept. † Initial mLoSSI/LoSDI represent the clinical activity and damage scores assessed prior to the initiation of any first-line systemic therapy (MTX with or without Prednisone). ‡ Concomitant therapy refers to background medications maintained during telitacicept treatment. Standard dosages used in this study: MTX, 10-15 mg/m² once weekly (oral); Prednisone, 1 mg/kg/day (oral). § Prednisone taper duration indicates the time taken to successfully discontinue oral corticosteroids after starting telitacicept.“—” indicates no prednisone was used during the study period; “Still on” indicates the patient is currently tapering.
2026-02-27 | Successful tocilizumab-based combination therapy for a case of rapidly progressive adult deep morphea with multiple antiphospholipid antibodies: a case report and literature review.
Localized Scleroderma (LoS), particularly aggressive subtypes such as Deep Morphea (morphea profunda), is a rare chronic autoimmune fibrosing disorder that can extend into the subcutaneous tissue, fascia, and muscle. These deep forms carry a high risk of functional impairment. Tocilizumab (TCZ), an anti-interleukin-6 (IL-6) receptor antibody, has emerged as a promising therapy for severe, refractory cases. However, its reported use typically follows the failure of standard immunosuppressive agents like methotrexate (MTX). We report the case of a 19-year-old male with a rapidly progressive deep morphea of the left lower extremity, with only a two-month history from onset. Initial symptoms included skin hardening, hyperpigmentation, and mild restriction of foot motion. Skin biopsy confirmed deep morphea, showing lymphoplasmacytic inflammation and eosinophilic fibrosis extending into the subcutaneous septa and muscle interstitium. Pre-treatment magnetic resonance imaging (MRI) revealed prominent edema (high T2 signal) in the subcutaneous fat and blurred muscle fascial planes, consistent with active deep inflammation. Uniquely, the patient was seropositive for multiple antiphospholipid antibodies (aPLs), including Lupus Anticoagulant (dRVVT ratio 1.34), anti-phosphatidylserine/prothrombin IgM (143.72 U), β2-glycoprotein I IgM (30.9 CU), and anticardiolipin IgM (28.2 CU). Given the rapid progression and deep tissue involvement, an early intensified combination regimen of TCZ (640 mg IV every 4 weeks), MTX (12.5 mg weekly), high-dose corticosteroids (IV pulses followed by 30 mg/day oral prednisone taper), and prophylactic aspirin (100 mg daily) was initiated. Follow-up MRI at six months showed a marked reduction in the deep tissue edema, correlating with significant clinical improvement in skin induration and tightening by nine months post-treatment. No serious adverse events were observed during follow-up. This case demonstrates the successful outcome of early TCZ-based combination therapy in rapidly controlling the aggressive inflammatory process of an adult deep morphea. The objective radiological response validates this early intervention strategy, which deviates from the typical second-line use of TCZ. Furthermore, the case highlights a rare but clinically important overlap between severe localized scleroderma and multiple aPL seropositivity.
2026-01-01 | Supplemental Figure: Longitudinal Assessment of Disease Activity and Damage Scores During Telitacicept Therapy in Pediatric Refractory JLS
This figure illustrates the individual clinical trajectories for the seven pediatric patients with refractory juvenile localized scleroderma (JLS) treated with telitacicept。The x-axis represents the duration of telitacicept treatment in weeks, and the y-axis represents the validated clinical scores。Red circles (●) and lines indicate the modified Localized Scleroderma Skin Severity Index (mLoSSI), representing active inflammation including erythema, skin thickness, and new lesion extension。Blue squares (■) and lines indicate the Localized Scleroderma Skin Damage Index (LoSDI), representing accumulated tissue damage such as atrophy, subcutaneous fat loss, and pigmentation changes。A consistent decline in mLoSSI scores was observed in most patients, signifying the suppression of active disease, while LoSDI scores generally stabilized, even in patients with extended follow-up such as Patient 6, whose data now includes a 48-week evaluation to demonstrate the durability of the clinical response。Note that Patient 1 (Panel A) discontinued treatment after 24 weeks due to a lack of subjective improvement despite the reduction in activity scores, and Patient 7 (Panel G) had a follow-up duration of 12 weeks at the time of analysis.
cell therapies
2026-07-14 | Redistribution of Gaze Patterns in Facial Localized Scleroderma Following Autologous Fat Transfer: An Eye-Tracking Study.
The study aimed to use eye-tracking technology objectively quantifying changes in visual attention patterns in observers viewing faces of patients with facial localized scleroderma (LoS) before and after autologous fat transplantation (AFT). In this retrospective observational study, preoperative and postoperative standardized photographs of 30 patients with facial localized scleroderma (LoS) were presented to 50 observers. Gaze data were recorded using an eye tracker. Fixation proportions were analyzed for all affected regions and for specific facial subunits. A total of 30,266 fixation points were recorded. Postoperatively, the fixation proportion on the affected hemiface significantly decreased by 4.92% (p<0.05), with a concomitant increase in fixations redirected toward the unaffected side. Furthermore, an increase of 2.39% (p<0.05) in fixation proportion was observed in the central T-zone (periorbital and nasal regions). Subunit analysis revealed reductions in fixations on the affected cheek (16.12% to 10.39%, p<0.05) and forehead (17.18% to 13.23%, p<0.05). Stratified analysis showed that severe dermal atrophy and severe dyspigmentation were associated with less postoperative fixation reduction, whereas fixation reduction did not differ significantly by subcutaneous atrophy severity. AFT alters observers' visual attention by reducing fixations on the affected facial areas and redirecting gaze toward the unaffected side and the central T-zone. This shift suggests a partial redistribution of social-perceptual gaze patterns toward a more typical facial viewing pattern. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
2026-03-09 | A novel microneedle-based delivery of NRF2-overexpressing exosomes for scleroderma therapy.
Scleroderma is a chronic autoimmune connective tissue disease characterized by progressive skin fibrosis, vascular dysfunction, and immune dysregulation. Current therapies remain largely ineffective in reversing established fibrosis and are limited by systemic side effects. In this study, we developed a novel therapeutic strategy combining microneedle (MN)-mediated transdermal delivery with NRF2-overexpressing exosomes (NRF2-OE Exos) to locally enhance antioxidant, anti-fibrotic, anti-inflammatory, and pro-angiogenic effects in scleroderma. Exosomes were isolated from NRF2-OE adipose-derived stem cells (ADSCs) and incorporated into GelMA/PEGDA-based dissolvable MNs. These MNs demonstrated excellent mechanical strength, minimal invasiveness, sustained exosome release, and efficient cellular uptake in vitro. Functional assays showed that NRF2-OE Exos-loaded MNs significantly enhanced endothelial tube formation, preserved fibroblast mitochondrial integrity, and promoted macrophage polarization toward a reparative phenotype. In a bleomycin-induced murine scleroderma model, MN treatment reduced dermal thickening, collagen deposition, and α-SMA expression while promoting vascular regeneration and immunomodulation. Mechanistically, transcriptomic analysis revealed that NRF2-OE Exos suppressed pro-fibrotic Wnt and Hippo signaling pathways and activated calcium and cAMP signaling pathways. Moreover, NRF2-OE Exos alleviated mitochondrial dysfunction and ferroptotic injury by upregulating antioxidant and lipid peroxidation defense genes. Collectively, this study demonstrates that MN-mediated delivery of engineered exosomes offers a promising, localized, and multifaceted therapeutic approach for scleroderma, with strong translational potential.
2026-01-01 | Fat Grafting and Dermal Fat Grafting for Localized Scleroderma of the Forehead: A Colorimetric Analysis of Surgical Outcomes
Objectives: Localized scleroderma (LS) is characterized by skin fibrosis and dyschromia. Fat grafting and dermal fat grafting are surgical options used to improve these features. In this study, we aimed to objectively compare postoperative color improvement between the two techniques using the CIEDE2000 (ΔE00) color difference formula.
2025-09-26 | Exploring the Therapeutic Potential of Adipose-Derived Stem Cells in Attenuating Skin Fibrosis: Insights from a Bleomycin-Induced Murine Model
BACKGROUND: Scleroderma, characterized by excessive collagen deposition and dysregulated immune responses, leads to debilitating skin fibrosis. Adipose-derived stem cells (ADSCs) exhibit antifibrotic and immunomodulatory properties, but their dynamic interactions within fibrotic microenvironments remain underexplored. This study investigates the temporal effects of ADSCs on skin fibrosis and elucidates their molecular mechanisms. METHODS: A bleomycin (BLM)-induced skin fibrosis model was established in C57BL/6J mice. GFP-labeled ADSCs were subcutaneously injected into fibrotic lesions, with follow-up analyses at days 1, 7, 14, and 21 post-injection. Histopathological evaluation (H&E, Masson’s trichrome, α-SMA staining), qRT-PCR, flow cytometry, and RNA sequencing were performed to assess fibrosis progression, inflammatory cytokine levels, and ADSC behavior. In vitro co-culture experiments with human scleroderma-derived fibroblasts validated key pathways. RESULTS: ADSCs localized preferentially to hair follicles and perivascular regions, with survival declining by day 21. BLM-induced dermal thickening, collagen disorganization, and α-SMA expression were significantly reduced by ADSC treatment (p<0.05). Proinflammatory cytokines (TNF-α, IL-6, IL-1β) surged post-BLM induction but decreased sharply after ADSC administration. RNA sequencing revealed time-dependent transcriptomic shifts: immunomodulatory pathways (e.g., IL-6 production, VEGF signaling) dominated at day 7, while antifibrotic pathways (collagen matrix regulation, TGF-β/Smad inhibition) emerged by day 14. TSG-6, a critical antifibrotic mediator, was upregulated in ADSCs within fibrotic environments. Silencing TSG-6 in ADSCs abolished their antifibrotic effects, restoring COL1 and α-SMA expression in fibroblasts (p<0.05). In vivo, TSG-6-deficient ADSCs failed to suppress TGF-β/Smad2/3 activation, confirming its pivotal role. CONCLUSION: ADSCs exert dual-phase therapeutic effects: early immunomodulation (days 1–7) followed by sustained antifibrotic action (days 14–21), mediated partly via TSG-6-dependent TGF-β/Smad pathway inhibition. These findings highlight ADSCs as a promising cell-based therapy for fibrotic skin disorders, offering insights into optimizing timing and mechanisms for clinical translation.
2025-09-24 | Injectable Immune-Regulating Mesenchymal Stem Cells Hydrogel for Localized Scleroderma Treatment.
Bioactive hydrogels with anti-inflammatory, antioxidant, and pro-angiogenic properties are crucial for unlocking the full potential of mesenchymal stem cells (MSCs) therapy for scleroderma treatment. Here, drawing inspiration from the adhesion, antioxidant, and inflammation regulation ability of green tea, we introduce an injectable MSCs hydrogel containing immune-regulating polyphenol nanozymes to treat localized scleroderma. The hydrogel is constructed based on the dynamic Schiff reaction, which could endow it with injectability, self-healing function, and tissue adhesion. The introduction of natural polyphenol-based nanozymes can enhance the reactive oxygen species (ROS) scavenging and anti-inflammatory capabilities of the hydrogel and facilitate macrophage transformation. Besides, the hydrogel provides a conducive three-dimensional (3D) growth environment for MSCs in vitro, effectively promoting the ability of MSCs in the antifibrosis, vascular endothelial cells migration, and neovascularization. We have demonstrated that our hydrogel could accelerate the recovery of scleroderma lesions by inhibiting the expression of pro-inflammatory and fibrotic factors, promoting angiogenesis, remodeling skin appendages, and enhancing the expression of anti-inflammatory factors in a mouse scleroderma model. These results suggest that our injectable polyphenol nanozyme MSCs hydrogel presents a potential therapeutic strategy for managing scleroderma.
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2025-04-25 | miR-143-3p boosts extracellular vesicles to improve the dermal fibrosis of localized scleroderma.
Localized scleroderma (LoSc) is an autoimmune disease that features extensive fibrosis of the skin. Due to its severity and limited understanding, no effective treatments have been developed to date. Bone marrow mesenchymal stem cells (BMSCs) derived extracellular vesicles (EVs) have been demonstrated promising therapeutic effects on the LoSc mouse model in our previous study. However, identifying the targets and underlying mechanisms of EVs remains a significant challenge for therapeutic applications. miR-143-3p, a critical and abundant factor in BMSC-EVs identified through miRNA sequencing, mediates antifibrotic effects in a LoSc mouse model and is significantly lacking in the dermis of LoSc patients. This microRNA inhibits myofibroblast formation and collagen synthesis, contributing to the therapeutic effects of BMSC-EVs in the LoSc mouse model. Moreover, miR-143-3p-reinforced BMSC-EVs demonstrated enhanced therapeutic efficacy compared to normal BMSC-EVs, reducing dermal thickening, collagen deposition, fibroblast differentiation into myofibroblasts, and promoting skin tissue remodeling. IGF1R, highly expressed in the skin of LoSc, was identified as a potential target of miR-143-3p and was inhibited by miR-143-3p-reinforced EVs, thereby modulating the IGF1/IGF1R-AKT/MAPK pathway. In conclusion, miR-143-3p-enriched EVs could be a more efficient candidate for treating dermal fibrosis in LoSc.
2024-11-22 | miR-3606-3p alleviates skin fibrosis by integratively suppressing the integrin/FAK, p-AKT/p-ERK, and TGF-β signaling cascades.
Fibroblast abnormalities are crucial causes of skin fibrosis, including systemic sclerosis (SSc) and keloids. However, their mechanisms, including underlying microRNA regulatory mechanisms, remain elusive. This study aimed to evaluate the roles, mechanisms, and therapeutic potential of miR-3606-3p in regulating multiple fibroblast abnormalities. The miR-3606-3p levels were evaluated in skin tissues and primary fibroblasts. RNA-seq and luciferase assays were employed to identify miR-3606-3p targets. Collagen contraction, western blotting, in vivo imaging, and real-time cellular analysis were used to assess fibroblast abnormalities. The therapeutic potential of miR-3606-3p was evaluated in mice. MiR-3606-3p decreased in skin tissues (SSc: Fold Change (FC) = - 2.95, P = 0.0101; keloid: FC = - 3.42, P < 0.0001) and primary fibroblasts (SSc: FC = - 12.74, P = 0.0278; keloid: FC = - 2.08, P = 0.0021) from skin fibrosis patients, and negatively correlated with disease severity. Mechanistically, miR-3606-3p targeted the 3'-untranslated regions (3'-UTRs) of Integrin αV (ITGAV), GRB2-associated binding protein 1 (GAB1), and transforming growth factor beta receptor 2 (TGFBR2), all of these three targets increased in skin fibrosis. Simultaneously, miR-3606-3p inhibited fibroblast's fibrogenesis, migration, inflammation, and proliferation by inhibiting ITGAV/integrin/FAK, GAB1/p-AKT/p-ERK, and TGFBR2/p-SMAD2/3 signaling. ITGAV-mediated integrin/FAK signaling unidirectionally activated the p-AKT/p-ERK and p-SMAD2/3 pathways. Knockdown of GAB1 and TGFRB2 reduced ITGAV-induced p-AKT/p-ERK and p-SMAD2/3 activities. MiR-3606-3p, si-ITGAV, si-GAB1, and si-TGFBR2 exhibited significant inhibition of fibrogenesis and migration. Inflammation was primarily inhibited by si-ITGAV and si-GAB1, while proliferation was primarily inhibited by si-TGFBR2. Moreover, miR-3606-3p significantly attenuates skin fibrosis in keloid-bearing mice. MiR-3606-3p is downregulated in skin fibrosis. Moreover, it negatively correlates with disease severity. Functionally, miR-3606-3p inhibits fibrogenesis, migration, inflammation, and proliferation of fibroblasts. Mechanistically, miR-3606-3p inhibits ITGAV, GAB1, and TGFBR2 by targeting their 3'-UTRs. ITGAV-, GAB1-, and TGFBR2-activated integrin/AKT/ERK/SMAD2/3 signaling induced fibroblast abnormalities. In vivo, miR-3606-3p inhibits skin fibrosis in mice. Therefore, the multi-targeting, multi-phenotypic regulatory properties of miR-3606-3p suggest its potential utility in clinical treatment.
2022-12-27 | Identification of lncRNA expression profiles in pediatric localized scleroderma.
The role and potential molecular mechanism of inflammatory cells in pediatric localized scleroderma are poorly investigated. In this study, we first investigated the profiling of inflammatory cells in skin samples from pediatric localized scleroderma. Among them, CD4+ T-cells were up-regulated. Co-culture dermal fibroblasts with CD4+ T-cells promoted fibrosis of fibroblasts. Candidate lncRNAs were further explored by lncRNAs-seq between the normal skin tissues and pediatric localized scleroderma tissues, and the lncRNAs-seq between fibroblasts co-cultured with CD4+ T lymphocytes and control fibroblasts. By comparing the two datasets, we identified eight up-regulated and three down-regulated lncRNAs, which were the potential lncRNAs for the phenotype of pediatric localized scleroderma. Here, we identified the CD4+ T-cells infiltration in pediatric localized scleroderma and potential lncRNAs for the treatment of pediatric localized scleroderma.
2022-06-27 | Elevated Alpha 1(I) to Alpha 2(I) Collagen Ratio in Dermal Fibroblasts Possibly Contributes to Fibrosis in Systemic Sclerosis.
Systemic sclerosis (SSc) is characterized by excessive collagen deposition in the skin and internal organs. Activated fibroblasts are the key effector cells for the overproduction of type I collagen, which comprises the α1(I) and α2(I) chains encoded by COL1A1 and COL1A2, respectively. In this study, we examined the expression patterns of α1(I) and α2(I) collagen in SSc fibroblasts, as well as their co-regulation with each other. The relative expression ratio of COL1A1 to COL1A2 in SSc fibroblasts was significantly higher than that in control fibroblasts. The same result was observed for type I collagen protein levels, indicating that α2(I) collagen is more elevated than α2(I) collagen. Inhibition or overexpression of α1(I) collagen in control fibroblasts affected the α2(I) collagen levels, suggesting that α1(I) collagen might act as an upstream regulator of α2(I) collagen. The local injection of COL1A1 small interfering RNA in a bleomycin-induced SSc mouse model was found to attenuate skin fibrosis. Overall, our data indicate that α2(I) collagen is a potent regulator of type I collagen in SSc; further investigations of the overall regulatory mechanisms of type I collagen may help understand the aberrant collagen metabolism in SSc.
2018-11-01 | Progranulin overproduction due to constitutively activated c-Abl/PKC-δ/Fli1 pathway contributes to the resistance of dermal fibroblasts to the anti-fibrotic effect of tumor necrosis factor-α in localized scleroderma
Dermal fibroblasts derived from patients with systemic sclerosis (SSc) overproduce progranulin (PGRN), an endogenous antagonist of tumor necrosis factor (TNF) receptors, due to the deficiency of transcription factor Fli1. Fli1 expression is also decreased in dermal fibroblasts derived from patients with localized scleroderma (LSc).To investigate the expression levels of PGRN and its contribution to the induction of pro-fibrotic phenotype in LSc dermal fibroblasts.PGRN expression levels were determined by immunohistochemistry and quantitative reverse transcription PCR in the skin of human subjects. The role of PGRN in fibroblast activation was examined with gene silencing technique. The involvement of c-Abl/protein kinase C (PKC)-δ/Fli1 pathway in the regulation of PGRN expression was investigated by immunoblotting.The expression levels of PGRN and TNF-α were elevated in LSc skin lesions compared with healthy control skin. LSc dermal fibroblasts were less responsive to the anti-fibrotic effect of TNF-α than normal dermal fibroblasts. Importantly, gene silencing of PGRN reversed the response to TNF-α in LSc dermal fibroblasts. Similar to SSc dermal fibroblasts, the inhibition of c-Abl/PKC-δ/Fli1 pathway by gene silencing of ABL1 or PRKCD significantly suppressed PGRN expression in LSc dermal fibroblasts.PGRN overproduction due to constitutively activated c-Abl/PKC-δ/Fli1 pathway may contribute to the resistance of LSc dermal fibroblasts to the anti-fibrotic effect of TNF-α, which may be involved in maintaining their pro-fibrotic phenotype under the pro-inflammatory condition, as is the case with SSc.
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Drug Discovery Landscape
3 orphan drug designations for Localized scleroderma.
3 orphan drug designations for Localized scleroderma.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
HDF-LV-RTS-MMP1 (human dermal fibroblasts genetically modified with LV-RTS-MMP1) and Veledimex | cell therapies | FDA | 2016-04-19 | — | Castle Creek Biosciences, LLC |
Peptide 144 TGF beta-1-inhibitor | peptides | FDA | 2006-04-26 | — | Digna Biotech, S.L. |
Peptide 144 TGF- ß1 inhibitor (TSLDASIIWAMMQN) | peptides | EMA | 2005-10-28 | — | Digna Biotech S.L. |
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