Fibroblasts from the growing margin of keloid scars produce higher levels of collagen I and III compared with intralesional and extralesional sites: clinical implications for lesional site-directed therapy

Syed, Farhatullah; Ahmadi, Elham; Iqbal, Syed Amir; Singh, Subir; McGrouther, Duncan Angus; Bayat, Ardeshir

doi:10.1111/j.1365-2133.2010.10048.x

Cited by 147 publications

(174 citation statements)

References 56 publications

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“…In this study, we evaluated the therapeutic potential of FGF-2 for long-standing HTS and analyzed the underlying mechanism. Gene expression analysis of fresh dermal tissues in HTS and intact skin showed that HTS tissue had significantly higher mRNA expression of type 1 and type 3 collagen, important components of the extracellular matrix in HTS, 25 and TGF-b, which is a pathogenic mediator in tissue fibrosis; 26 but the expression of MMP-1, a collagenase that mainly digests interstitial collagen type 1 and 3, was significantly lower; these results are consistent with previous reports analyzing tissue fibrosis. 27,28 Gene expression of other collagenases, MMP-8 and MMP-13, were preliminary measured in fresh samples, but expression level of them were nearly at an undetectable level (data not shown).…”

Section: Discussionsupporting

confidence: 90%

Therapeutic potential of fibroblast growth factor-2 for hypertrophic scars: upregulation of MMP-1 and HGF expression

Eto

Suga

Aoi

et al. 2012

Laboratory Investigation

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Although hypertrophic scars (HTSs) and keloids are challenging problems, their pathogenesis is not well understood, making therapy difficult. We showed that matrix metalloproteinase (MMP)-1 expression was downregulated in HTS compared with normal skin from the same patients, whereas type 1 and 3 collagen and transforming growth factor-b (TGF-b) were upregulated. These differences, however, were not seen in cultured fibroblasts, suggesting the involvement of microenvironmental factors in the pathogenesis of HTS. Fibroblast growth factor-2 (FGF-2) highly upregulated the expression of MMP-1 and hepatocyte growth factor (HGF) in both HTS-derived and control fibroblasts; the upregulation was reversed by extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) inhibitors. An animal study using human HTS tissue implanted into nude mice indicated that controlled-release FGF-2 resulted in significantly less weight and decreased hydroxyproline content in HTS. Degradation of collagen fibers in FGF-2-treated HTS was also confirmed histologically. Western blotting showed that FGF-2-treated HTS expressed significantly higher MMP-1 protein than control. Decreased MMP-1 expression may be an important transcriptional change in HTS, and its reversal as well as upregulation of HGF by FGF-2 could be a new therapeutic approach for HTS.

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Section: Discussionsupporting

confidence: 90%

Therapeutic potential of fibroblast growth factor-2 for hypertrophic scars: upregulation of MMP-1 and HGF expression

Eto

Suga

Aoi

et al. 2012

Laboratory Investigation

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“…A number of ECM molecules are involved in tissue remodelling, the majority of these such as collagen I, fibronectin and other glycosaminoglycans are increased in KD (1); however, the reasons for dysregulated HAS and HYAL expression, their role in lower HA concentrations in KD tissue and any subsequent effect in vivo remain elusive. The study of KD in whole tissue is more relevant than cell culture, as the interaction between different cell types and the ECM may be investigated (15), expression patterns also vary between the margin and the middle of the KD lesion (16).…”

Section: Discussionmentioning

confidence: 99%

Altered expression of hyaluronan synthase and hyaluronidase mRNA may affect hyaluronic acid distribution in keloid disease compared with normal skin

Sidgwick

Iqbal

Bayat

2013

Experimental Dermatology

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Keloid disease (KD) is a fibroproliferative disorder characterised partly by an altered extracellular matrix (ECM) profile. In fetal scarring, hyaluronic acid (HA) expression is increased, but is reduced in KD tissue compared with normal skin (NS). The expression of Hyaluronan Synthase (HAS) and hyaluronidase (HYAL) in KD and NS tissue were investigated for the first time using a range of techniques. Hyaluronan synthase and HYAL mRNA expression were significantly increased in NS tissue compared with KD tissue (P < 0.05). Immunohistological analysis of tissue indicated an accumulation of HAS and HYAL protein expression in KD compared with NS due to the thicker epidermis. No differences were observed in mRNA or protein expression in KD and NS fibroblasts. Reduced expression of HAS and HYAL may alter HA synthesis, degradation and accumulation in KD. Better understanding of the role of HA in KD may lead to novel therapeutic approaches to address the resulting ECM imbalance.Abbreviations: KD, keloid disease; NS, normal skin; ECM, extracellular matrix; HA, hyaluronic acid; HAS, hyaluronan synthase; HYAL, hyaluronidase; DMEM, dulbecco's modified eagle medium; DAPI4′ 6-diamidino-2-phenylindole.

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“…However, keloid is not an autoimmune disease, and it is still controversial whether the collagen production by keloid fibroblasts is also upregulated (12)(13)(14)(15). Thus, different factors are likely to mediate the tissue fibrosis in SSc/LSc and keloid, but the exact mechanism involved in each fibrotic condition is still unknown.…”

mentioning

confidence: 99%

The Downregulation of microRNA let-7a Contributes to the Excessive Expression of Type I Collagen in Systemic and Localized Scleroderma

Makino

Jinnin

Hirano

et al. 2013

The Journal of Immunology

146

111

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Systemic and localized scleroderma (SSc and LSc) is characterized by excessive deposition of collagen and tissue fibrosis in the skin. Although they have fundamental common characteristics including autoimmunity, little is known about the exact mechanism that mediates the excessive collagen expression in these disorders. In the current study, we tried to evaluate the possibility that microRNAs (miRNAs) play some roles in the pathogenesis of fibrosis seen in these diseases. miRNA expression patterns were evaluated by miRNA array analysis, real-time PCR, and in situ hybridization. The function of miRNAs in dermal fibroblasts was assessed using miRNA inhibitors, precursors, or protectors. In the mouse model of bleomycin-induced dermal sclerosis, the overexpression of miRNAs was performed by i.p. miRNA injection. We demonstrated let-7a expression was downregulated in SSc and LSc skin both in vivo and in vitro, compared with normal or keloid skin. The inhibition or overexpression of let-7a in human or mouse skin fibroblasts affected the protein expression of type I collagen or luciferase activity of collagen 3′-untranslated region. Also, we found let-7a was detectable and quantitative in the serum and investigated serum let-7a levels in patients with SSc or LSc. let-7a concentration was significantly decreased in these patients, especially in LSc patients. Moreover, we revealed that the intermittent overexpression of let-7a in the skin by i.p. miRNA injection improved the skin fibrosis induced by bleomycin in mice. Investigation of more detailed mechanisms of miRNA-mediated regulation of collagen expression may lead to new therapeutic approaches against SSc and LSc.

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Fibroblasts from the growing margin of keloid scars produce higher levels of collagen I and III compared with intralesional and extralesional sites: clinical implications for lesional site-directed therapy

Cited by 147 publications

References 56 publications

Therapeutic potential of fibroblast growth factor-2 for hypertrophic scars: upregulation of MMP-1 and HGF expression

Therapeutic potential of fibroblast growth factor-2 for hypertrophic scars: upregulation of MMP-1 and HGF expression

Altered expression of hyaluronan synthase and hyaluronidase mRNA may affect hyaluronic acid distribution in keloid disease compared with normal skin

The Downregulation of microRNA let-7a Contributes to the Excessive Expression of Type I Collagen in Systemic and Localized Scleroderma

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