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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

The hard problem: Mechanotransduction perpetuates the myofibroblast phenotype in scleroderma fibrosis. Fibrotic myofibroblasts possess an intrinsically activated pro-adhesive signaling pathway, and that this contributes to the perpetuation of pathological fibrosis. PubMed, Wound Repair Regen, 01/07/2021.

Machine learning integration of scleroderma (SSc) histology and gene expression identifies fibroblast polarisation as a hallmark of clinical severity and improvement. CD34 and aSMA stains describe distinct fibroblast polarisation states and may be useful biomarkers of clinical severity and improvement in diffuse SSc. PubMed, Ann Rheum Dis, 10/07/2020. (Also see Genetics)

Translational engagement of lysophosphatidic acid receptor 1 (LPA1) in skin fibrosis: from dermal fibroblasts of patients with scleroderma to tight skin 1 mouse. Our results support the therapeutic potential of LPA1 receptor antagonists in systemic sclerosis. PMC, Br J Pharmacol, 2020 Sep; 177(18): 42964309. (Also see Skin Fibrosis)

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)

(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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