Fibrosing connective tissue disorders of the skin: Molecular similarities and distinctions
Abstract
A variety of fibrosing connective tissue disorders of the skin have been described. They all share a characteristic activation of fibroblasts resulting in excessive production and deposition of extracellular matrix whereas their etiologies, incidence rates and clinical appearances differ dramatically in part. As effective treatment options are still not on hand, the understanding of cutaneous fibrogenesis needs to be improved. This review focuses on the molecular differences and similarities of the major fibrosing skin disorders namely systemic sclerosis, localized scleroderma, keloid and hypertrophic scars, Eosinophilic fasciitis, Lichen sclerosus and graft-versus-host-disease. Abnormalities in ECM turnover and the impact of matrix-metalloproteases were closely examined. It could be concluded, that besides increased collagen synthesis, modified ECM degradation is an as important factor in cutaneous fibrogenesis. The influence of immune components such as HLA haplotypes and the production of auto-antibodies is crucial for some of the diseases, but not decisive for skin fibrosis in general. A great number of cytokines was reported to be differentially regulated in the respective disorders among whom the components of the gp130/STAT3 signaling pathway seem to be of pivotal importance. Furthermore, the role of miRNAs in the pathogenesis of fibrosing connective tissue diseases of the skin was analyzed according to the current state of knowledge. In summary, this review gives an explicit overview of the various molecular mechanisms leading to fibrosis in the skin and the underlying connective tissue and reveals the most promising targets for future therapeutic approaches.
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Keloids and hypertrophic scars can be histologically differentiated by their arrangement of collagen fibers, presence of αSMA-positive myofibroblasts, and extent of angiogenesis.
“Furthermore, keloids and hypertrophic scars can be histologically differentiated by their diverse arrangement of collagen fibers, presence of α-smooth muscle actin (αSMA)–positive myofibroblasts, and extent of angiogenesis (16).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [16]
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miR-218 regulates focal adhesion kinase–dependent TGFβ signaling in fibroblasts
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“Connective tissue is largely composed of extracellular matrix (ECM) and fibroblasts (Canady et al., 2013).”
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“Further, hyaluronan markedly accumulates within the epidermis and dermis, in particular around blood vessels [297].”
BackgroundInfluentialZhang, Y., Wang, J., Zhou, S., Xie, Z., Wang, C., Gao, Y., Zhou, J., Zhang, X., & Li, Q. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1333-7 · Cited by 27 · see citing works
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“The involvement of X chromosome monosomy (104), the influence of HLA haplotypes (105), the specific HLA classes are associated with localized scleroderma (106).”
BackgroundShi, J., Wu, Y., Guo, S., Zhang, H., Chen, G.-T., & Xu, X. (2018) · Drug Development and Industrial Pharmacy · doi:10.1080/03639045.2018.1546315 · Cited by 26 · see citing works
“During the wound healing process, there is an imbalance in the secretion of cytokines such as transforming growth factor-b (TGF-b) [7–9], vascular endothelial growth factor (VEGF) [10–14], fibroblast growth factor (FGF) [15], epidermal growth factor (EGF) [16] , tumor necrosis factor-a (TNF-a) [17,18], and several int…”
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“For instance, skin fibrotic disorders including scleroderma, keloids, and hypertrophic scars, impair skin function and appearance and remain incurable [3].”
BackgroundEosinophilic fasciitis and lichen sclerosus in a patient treated with nivolumab
Andrés‐Lencina, J., Burillo‐Martínez, S., Aragón‐Miguel, R., Calleja‐Algarra, A., Rodríguez‐Peralto, J., Ortiz‐Romero, P., & Gargallo‐Moneva, V. (2018) · Australasian Journal of Dermatology · doi:10.1111/ajd.12836 · Cited by 23 · see citing works
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“Both activins are involved in Smad 2/3 signalling and consequently play a role in fibrosis (Werner and Alzheimer, 2006; Canady et al., 2013; Walton et al., 2017; Itoh et al., 2018).”
BackgroundPerspective on Stem Cell Therapy in Organ Fibrosis: Animal Models and Human Studies
Wiśniewska, J., Sadowska, A., Wójtowicz, A., Słyszewska, M., & Szóstek-Mioduchowska, A. Z. (2021) · Life · doi:10.3390/life11101068 · Cited by 20 · see citing works
“Moreover, membrane-bound matrix metalloproteinase (MT1-MMP)-deficient mice that show a deficiency of membrane-type MMP-14, the metalloproteinase responsible for pericellular proteolysis of ECM, develop progressive fibrosis of the dermis and hair follicles [26].”
BackgroundInfluentialProtease Activated Receptor-1 Deficiency Diminishes Bleomycin-Induced Skin Fibrosis
Duitman, J., Ruela-de-Sousa, R. R., Shi, K., de Boer, O. J., Borensztajn, K., Florquin, S., Peppelenbosch, M. P., & Spek, C. A. (2014) · Molecular Medicine · doi:10.2119/molmed.2014.00027 · Cited by 19 · see citing works
Morphological Clues in the Diagnosis of Sclerodermiform Dermatitis
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“Several fibrosing connective tissue disorders of the skin share the characteristic activation of fibroblasts that results in increased production and deposition of collagen (Canady et al., 2013).”
BackgroundSelf-citationEpidermal Potentiation of Dermal Fibrosis
Dolivo, D., Sun, L. S., Rodrigues, A. E., Galiano, R. D., Mustoe, T. A., & Hong, S. J. (2023) · American Journal Of Pathology · doi:10.1016/j.ajpath.2023.01.008 · Cited by 15 · see citing works
Expression of galectin‑7 in vulvar lichen sclerosus and its effect on dermal fibroblasts
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“To the best of our knowledge, no suitable animal models for Lichen sclerosus have been produced previously (29).”
Therapeutic potential of agents targeting cannabinoid type 2 receptors in organ fibrosis
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“Fibrotic skin disorders are often characterized by abnormal collagen deposition in the skin and/or fascia, regularly causing significant morbidity [1,2].”
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“alone indicated a significant increase in the expression of FAP , ACTA2 , COL1A1 , COL1A2 , and FN1 genes (Figure 5).”
BackgroundInfluentialMorfea o esclerodermia localizada
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“(2013) [7], Jacobe H, Ahn C, Arnett FC, Reveille JD.”
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Wound repair and scarring of genital skin
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“Furthermore, chronic genital inflammatory conditions such as LSC are characterized by decreased elastic fibres, tissue fibrosis and atrophy([25,30]).”
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“19,40 In LS, there is a discernible alteration in the composition of T cells and fibroblasts, 5,11,17,22,41 a phenomenon our research corroborates.”
Is diet related to skin condition? A Mendelian randomization study
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“3) (detailed analysis results are provided in Supplementary Table 8, 9).”
InfluentialEosinophilic fasciitis: A case report
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“[16]”
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Investigating the role of microRNAs in hypertrophic and keloid scar formation
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Additional Treatment Modality to Improve Outcomes in Myocardial Infarctions and Strokes
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“This topic has not been studied in depth yet [9] [10].”
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“…considerable advances, this pathology, which affects several million of individuals worldwide, is still without a specific and effective therapy (Canady et al., 2013) The ancient dogma that fibrosis originates from hyperactivation or deregulation of tissue resident fibroblasts by the local…”
BackgroundEosinophilic fasciitis. Nosological location Fascitis eosinofílica. Ubicación nosológica
Rossi, G. C., Paskaukas, G., Simionato, C., Marini, M., & Vigovich, F. (2015)
Fascitis eosinofílica: reporte de un caso
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The role of nerve growth factor in epidermal wound repair in a human skin ex vivo model
Nasir, M. H. M., & binti, N. A. (2019)
Regenerative medicine of the skin: Quantitative and qualitative analyses
Oostendorp, C. (2019) · Radboud Repository (Radboud University)
Condorelli, A. G., El Hachem, M., Zambruno, G., Nyström, A., Candi, E., & Castiglia, D. (2021) · Figshare · doi:10.6084/m9.figshare.14562729
Pirfenidone-exosomes as innovative strategies for scarless tissue repair in wound healing
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Microbiota-derived butyrate promotes dermal collagen production through epidermal-dermal crosstalkPreprint
Pan, J. T.-C., Murga-Garrido, S. M., Minzaghi, D., White, E. K., Huang, S., Uberoi, A., & Grice, E. A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.15.731906
“Excessive collagen deposition causes fibrotic skin conditions, such as scleroderma, hypertrophic scarring, and keloids 20 .”
Skin Regeneration IV: Wound Healing—Repair and Regeneration—
Nanba, D. (2026) · Journal of Society of Cosmetic Chemists of Japan · doi:10.5107/sccj.60.69
Cavalheiro, D. D. A. P. H., Chuery, A. C. S., Enokihara, M. M. S. E. S., Miot, H. A., Fillippini, M., & Speck, N. M. D. G. (2026) · Lasers in Medical Science · doi:10.1007/s10103-026-04923-3
“It is known that the formation of sclerotic tissue in LS involves multiple pathways [ 1, 17, 18] and it is speculated that collagen increase observed in cases of VLS may reflect poor immunogenic tissue repair response to the disappearance of elastic fibers in the superficial dermis [ 19].”
- Authors
- Canady, J., Karrer, S., Fleck, M., & Bosserhoff, A. K.
- Affiliations
- University of Regensburg (DE)
- Venue
- Journal of Dermatological Science
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 70
- Issue
- 3
- Pages
- 151-158
- ISSN
- 0923-1811 (ISSN-L)
- OpenAlex
- W1966782365
- Cited by
- 66
- References
- 93
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 3 · 2021: 6 · 2020: 3 · 2019: 6 · 2018: 11 · 2017: 7 · 2016: 1 · 2015: 5 · 2014: 10
- FWCI
- 0.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Dermatological Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Health Sciences › Medicine › Dermatology › Dermatologic Treatments and Research
- Health Sciences › Medicine › Rheumatology › Dupuytren's Contracture and Treatments
- Keywords
- skin fibrosis, systemic sclerosis, morphea, keloids, hypertrophic scars, eosinophilic fasciitis, lichen sclerosus, graft-versus-host disease, extracellular matrix turnover, matrix metalloproteinases, collagen synthesis, HLA haplotypes, autoantibodies, cytokines, microRNA, fibroblast activation
- MeSH terms
- Connective Tissue Diseases, Extracellular Matrix, Fibrosis, Humans, Skin, Skin Diseases, Signal Transduction
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