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

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™))

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.

Multiplex cytokine analysis of dermal interstitial blister fluid defines local disease mechanisms in systemic sclerosis (SSc). An immuno-inflammatory environment and aberrant vascular repair are intimately linked to fibroblast activation in lesional skin in SSc. Arthritis Research and Therapy, 03/23/2015.

A reactive oxygen species(ROS)-mediated loop maintains the increased expression of NOX2 and NOX4 in skin fibroblasts from patients with systemic sclerosis (SSc). NOX2 and NOX4 generate ROS in SSc fibroblasts and play a critical role in cell activation and DNA damage. PubMed, Arthritis Rheumatol, 02/23/2015.

Role of Cellular Senescence and NOX4-Mediated Oxidative Stress in Systemic Sclerosis (SSc) Pathogenesis. Numerous studies have implicated oxidative stress in SSc pathogenesis, suggesting a plausible mechanism in which excessive oxidative stress induces cellular senescence and that the molecular events play an important role in the fibrotic and fibroproliferative vasculopathy characteristic of SSc. PubMed, Curr Rheumatol Rep, 2015 Jan;17(1):473.

Fibroblasts in fibrosis: novel roles and mediators. In addition to the extensive extracellular matrix fibroblasts have multiple concomitant biological roles, such as in wound healing, inflammation, and angiogenesis, which are each interwoven with the process of fibrosis. Pub Med Front Pharmacol, 2014 May 27;5:123. (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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