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

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)

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.

Scleroderma (SSc) peripheral B lymphocytes secrete interleukin-6 and TGF–ß and activate fibroblasts. Peripheral B lymphocytes from SSc patients secreted IL-6 and TGF–ß, and activated fibroblasts in vitro. PubMed, Arthritis Rheumatol, 12/19/2016. (Also see Interleukins)

Bosentan and macitentan (ERA's) prevent the endothelial–to–mesenchymal transition (EndoMT) in systemic sclerosis: in vitro study. The present study provides further in vitro evidence of the use of ERA in inhibiting the EndoMT process, supporting the clinical efficacy of these drugs in SSc therapy and their usefulness for interfering with progressive fibrosis. PMC, Arthritis Res Ther, October 2016; 18: 228. (Also see Tracleer (Bosentan) and Macitentan (Opsumit™))

Expression of the endocannabinoid receptors in human fascial tissue. The endocannabinoid receptors of fascial fibroblasts can contribute to modulate the fascial fibrosis and inflammation. PubMed, Eur J Histochem, 2016 Jun 28;60(2):2643. (Also see Endocannabinoid System)

Mechanistic insight into the norepinephrine (NE)–induced fibrosis in systemic sclerosis (SSc). These results suggest that cold exposure and/or emotional stress–induced NE might contribute to the skin fibrosis via potentiation of IL-6 production from fibroblasts in SSc. PMC, Sci Rep, 2016; 6: 34012. (Also see Interleukins)

Tribbles homologue 3 stimulates canonical TGF-ß signalling to regulate fibroblast activation and tissue fibrosis. The present study characterises TRB3 as a novel profibrotic mediator in systemic sclerosis. PubMed, Ann Rheum Dis, 2016 Mar;75(3):609-16. (Also see Molecular Defect)

Toll–like receptor 9 (TLR9) signaling is augmented in systemic sclerosis (SSc) and elicits transforming growth factor–ß (TGF–ß)–dependent fibroblast activation. In patients with SSc, mitochondrialDNA and other damage–associated TLR9 ligands in the skin might trigger localized activation of TLR9 signaling, TGF–ß production and consequent fibroblast activation. PubMed, Arthritis Rheumatol, 03/04/2016.


(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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