Causes of Scleroderma: Fibroblasts

Author: Shelley Ensz. Scleroderma is highly variable. See Types of Scleroderma. Read Disclaimer


Abstract painting by Janet PaulmennFibroblasts are the most common cells of connective tissue. They produce the fibrous protein called collagen. "The major source of fibrosis in SSc is over production of collagens from fibroblasts."(1) ISN. (Also see What is Scleroderma? and Causes of Scleroderma)

Fibroblasts. Fibroblasts provide a structural framework (stroma) for many tissues, and play a critical role in wound healing. They are the most common cells of connective tissue in animals. Wikipedia

CD47 prevents the elimination of diseased fibroblasts in scleroderma. Our study demonstrates the efficiency of combining different immunotherapies in treating scleroderma and provides a rationale for combining CD47 and IL-6 inhibition in clinical trials. PubMed, JCI Insight, 2020 Aug 20;5(16):140458.

TLY012 Receives FDA Orphan Drug Status for Systemic Scleroderma. An early study showed that TLY012 killed skin myofibroblasts from people with scleroderma, while it did not have the same effect in cells derived from people without the disease. Scleroderma News, 05/31/2020.

Effect of a monocyte chemoattractant protein-1 synthesis inhibitor on fibroblasts from patients with carpal tunnel syndrome (CTS). These results suggest that Bindarit in combination with SD208 may be beneficial as medical therapy for the subsynovial connective tissues fibrosis associated with CTS. PubMed, J Orthop Sci, 04/18/2020. (Also see Hand and Joint Involvement)

Kelch-like protein 42 is a pro-fibrotic ubiquitin E3 ligase involved in in systemic sclerosis (SSc). Our findings indicate that the KLHL42-PPP2R5e axis controls pro-fibrotic signaling in SSc lung fibroblasts. PubMed, J Biol Chem, 02/17/2020.

Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH. Our data indicate that the EZH2-dependent epigenetic phenotype of myofibroblasts is driven by HOTAIR. PubMed, Ann Rheum Dis, 02/10/2020.

Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis (SSc). DPP-4 characterizes a population of activated fibroblasts and shows that DPP-4 regulates TGFβ-induced fibroblast activation in the fibrotic skin of SSc patients. PubMed, Arthritis Rheumatol, 2020 Jan;72(1):137-149.

Antibodies against specific extractable nuclear antigens (ENAs) as diagnostic and prognostic tools and inducers of a profibrotic phenotype in cultured human skin fibroblasts: are they functional? This study suggests a pathogenic role of scleroderma-specific autoantibodies to directly induce pro-fibrotic activation in human dermal fibroblasts. PubMed, Arthritis Res Ther, 2019 Jun 24;21(1):152. (Also see Antibodies)

Endothelial to Mesenchymal Transition (EndMT): Role in Physiology and in the Pathogenesis of Human Diseases. The identification of molecules and regulatory pathways involved in EndMT and the discovery of specific EndMT inhibitors should provide novel therapeutic approaches for various human disorders mediated by EndMT. PubMed, Physiol Rev, 2019 Apr 1;99(2):1281-1324. (Also see Tracleer (Bosentan) and Macitentan (Opsumit™))

Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma. In vivo, TLY012 reverses established skin fibrosis to near–normal skin architecture in mouse models of scleroderma. PubMed, Nat Commun, 2019 Mar 8;10(1):1128.

Identification of regulators of the myofibroblast phenotype of primary dermal fibroblasts from early diffuse systemic sclerosis (dSSc) patients. Our results demonstrated the value of carefully–phenotyped SSc dermal fibroblasts as a platform for SSc target and drug discovery. PubMed, Sci Rep, 2019 Mar 14;9(1):4521.

Evolving insights into the cellular and molecular pathogenesis of fibrosis in systemic sclerosis (SSc). After reviewing the major and emerging cellular and molecular mechanisms underlying SSc, this article looks to identify clinical applications where this new molecular knowledge may allow for targeted treatment and personalized medicine approaches. PubMed, Transl Res, 02/23/2019.

PU.1 controls fibroblast polarization and tissue fibrosis. Pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs. PubMed, Nature, 01/30/2019.

Immune complexes (ICs) containing scleroderma (SSc)–specific autoantibodies induce a profibrotic and proinflammatory phenotype in skin fibroblasts. These data provide the first demonstration of the proinflammatory and profibrotic effects of SSc–ICs on fibroblasts, suggesting the potential pathogenicity of SSc autoantibodies. PubMed, Arthritis Res Ther, 2018 Aug 29;20(1):187. (Also see Antibodies in Systemic Scleroderma)

An orally–active adiponectin receptor agonist mitigates cutaneous fibrosis, inflammation and microvascular pathology in a murine model of systemic sclerosis (SSc). In vitro, AdipoRon abrogated profibrotic responses elicited by TGF-ß in normal fibroblasts, and reversed the inherently–activated profibrotic phenotype of SSc fibroblasts. PubMed, Sci Rep, 2018 Aug 7;8(1):11843.

Insights into myofibroblasts and their activation in scleroderma: opportunities for therapy? This review outlines the increasing complexity of the biological processes that leads to the appearance of the myofibroblast in normal functions and in diseased tissues. PubMed, Curr Opin Rheumatol, 07/31/2018.

TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung. The results suggest that systemic scleroderma patients with high TLR4 activity might show optimal therapeutic response to selective inhibitors of MD2/TLR4 complex formation. PubMed, JCI Insight, 2018 Jul 12;3(13). (Also see Skin Fibrosis and Pulmonary Fibrosis Research)

Methyl-CpG-binding protein 2 (MeCP2) mediates antifibrotic effects in scleroderma (SSc) fibroblasts. This study demonstrates a novel role for MeCP2 in skin fibrosis and identifies MeCP2-regulated genes, which can be potentially targeted for therapy in SSc. PubMed, Ann Rheum Dis, 05/14/2018. (Also see Skin Fibrosis)

Anti-elastase and anti-collagenase potential of Lactobacilli exopolysaccharides (LEPS) on human fibroblast. By consideration of high anti–collagenase, anti–elastase, antioxidant activity and wound healing of LEPS, they could be considered as good candidate of skin anti–aging agents for tissue engineering and skin regeneration scaffolds. PubMed, Artif Cells Nanomed Biotechnol, 2018 Feb 27:1-11. (Also see Wound Healing in Systemic Scleroderma)

Pushing cells to self–destruct combats deadly fibrosis. New research offers clues for how to selectively destroy the cells known as myofibroblasts that drive the condition. Science Magazine, 12/13/2017.

The Antiretroviral nelfinavir mesylate (NFV), a potential therapy for systemic scleroderma. NFV abrogates TGF–ß1–mediated myofibroblast differentiation and pulmonary fibrosis through off–target protein binding and supports consideration of this FDA–approved medication as an anti–fibrotic agent. PubMed, Arthritis Rheumatol, 09/21/2017. (Also see Treatments for Pulmonary Fibrosis)

Downregulation of Aquaporin3 in Systemic Sclerosis (SSc) Dermal Fibroblasts. SSc manifestations like skin dryness, abnormal wound healing, and fibrotic lesions may be related to downregulation of AQP3 in SSc fibroblasts. PubMed, Iran J Allergy Asthma Immunol, 2017 Jun;16(3):228-234.

Unifying mechanism for different fibrotic diseases. Here, we demonstrate that many endstage fibrotic diseases converge in the activation of the Activator protein 1 transcription factor c-JUN in the pathologic fibroblasts. PubMed, Proc Natl Acad Sci U S A, 2017 May 2;114(18):4757-4762.

Innate Immunity in Systemic Sclerosis (SSc). Currently, no effective therapy exists and exploiting the innate immune system perturbation may be one possible avenue. Innate immune dysregulation is key in SSc pathogenesis and may represent a novel target. PubMed, Curr Rheumatol Rep, 2017 Jan;19(1):2.

Transforming growth factor beta (TGF–beta1), int/Wingless (WNT) and sonic hedgehog (SHH) signaling in tumor progression and in fibrotic diseases. In this review, we focus on TGF–beta, WNT and SHH signal transduction pathways and describe small molecule inhibitors that are used in phase I/II clinical trials to treat fibrosis or fibrotic cancers. PubMed, Front Biosci (Schol Ed), 2017 Jan 1;9:31-45.

(1) Xiong M, Arnett FC, Guo X, Xiong H, Zhou X (2008) Differential Dynamic Properties of Scleroderma Fibroblasts in Response to Perturbation of Environmental Stimuli. PLoS ONE 3(2): e1693.

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