elastin and Keloid

To provide information about the clinical presentation of hypertrophic scars and keloids based on their varied structural components.. This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care.. After completing this continuing education activity, you should be able to: ABSTRACT: Hypertrophic scars and keloids are firm, raised, erythematous plaques or nodules that manifest when the cicatrix fails to properly heal. They result from pathologic wound healing and often cause pain and decreased quality of life. The appearance of such cosmetically unappealing scars affects the confidence and self-esteem of many patients. These scars can also cause dysfunction by interfering with flexion and extension across joints. Both possess some unique and distinct histochemical and physiologic characteristics that set them apart morphologically and at the molecular level. While these entities have been the focus of research for many years, differentiating between them remains challenging for clinicians.This article reviews the clinical presentation of aberrant scars and illustrates how they can be differentiated. It outlines their pathophysiology and emphasizes the unique molecular mechanisms underlying each disorder. It also examines how altered expression levels and the distribution of several factors may contribute to their unique clinical characteristics and presentation. Further research is needed to elucidate optimal treatments and preventive measures for these types of aberrant scarring.

Topics: Biopsy, Needle; Cicatrix, Hypertrophic; Collagen; Combined Modality Therapy; Diagnosis, Differential; Disease Progression; Education, Medical, Continuing; Elastin; Female; Fibrillin-1; Humans; Immunohistochemistry; Keloid; Male; Prognosis; Risk Assessment; Severity of Illness Index; Wound Healing; Wounds and Injuries

Elastin is rapidly deposited during late gestation in resilient tissues such as the arteries, lungs and skin owing to increased concentration of its mRNA. Pathological states can arise from congenital insufficiency or disorganization of elastin (cutis laxa). Other elastin deficiencies may be due to excess elastolysis or gene dosage effects. In the former, high turnover rates can be assessed by measurements of elastin degradation products in urine. Excess elastin accumulation by skin fibroblasts is characteristic of genetic diseases such as Buschke-Ollendorff syndrome, Hutchinson-Gilford progeria and keloid. Elastin expression is modulated by peptide growth factors, steroid hormones and phorbol esters, among which transforming growth factor beta (TGF-beta) is an especially potent up-regulator, acting largely through stabilization of mRNA. Recent evidence indicates cutis laxa fibroblasts that express little or no elastin have normal transcriptional activity but abnormal rates of elastin mRNA degradation. This defect is substantially reversed by TGF-beta through mRNA stabilization. Current studies explore the hypothesis that stability determinants lie within the 3' untranslated region of elastin mRNA. Post-transcriptional control of elastin expression appears to be a major regulatory mechanism.

Topics: Animals; Cutis Laxa; Elastin; Fibrosis; Humans; Keloid; Progeria

Topics: Animals; Basement Membrane; Cattle; Collagen; Connective Tissue; Ehlers-Danlos Syndrome; Elastin; Epidermolysis Bullosa; Fibroblasts; Glycopeptides; Humans; Keloid; Lysine; Marfan Syndrome; Metabolism, Inborn Errors; Microbial Collagenase; Mixed Function Oxygenases; Progeria; Protein Biosynthesis; Pseudoxanthoma Elasticum; Wound Healing

Keloids are benign tumours caused by abnormal wound healing driven by increased expression of cytokines, including activin A. This study compared effects of activins on normal and keloid-derived human dermal fibroblasts and investigated a novel treatment for keloids using follistatin. Normal skin and keloid tissue samples from 11 patients were used to develop primary fibroblast cultures, which were compared in terms of their histology and relevant gene (qRT-PCR and RNAseq) and protein (ELISA) expression. Activin A (INHBA) and connective tissue growth factor (CTGF) gene expression were significantly upregulated in keloid fibroblasts, as was activin A protein expression in cell lysates and culture medium. Activator protein 1 inhibitor (SR11302) significantly decreased INHBA and CTGF expression in keloid fibroblasts and a single treatment of follistatin over 5 days significantly inhibited activin and various matrix-related genes in keloid fibroblasts when compared to controls. Follistatin, by binding activin A, suppressed CTGF expression suggesting a novel therapeutic role in managing keloids and perhaps other fibrotic diseases.

Topics: Cells, Cultured; Connective Tissue Growth Factor; Elastin; Fibroblasts; Follistatin; Gene Expression; Humans; Inhibin-beta Subunits; Interleukin-6; Keloid; Plasminogen Activator Inhibitor 1; Retinoids; Up-Regulation

Mortalin (Mot) is a mitochondrial chaperone of the heat shock protein 70 family and it's pro-proliferative and anti-apoptosis functions could be associated with keloid pathogenesis, and blocking of mortalin and its interaction with p53 might be a potential novel target for the treatment of keloid. Therefore, we generated mortalin-specific small hairpin (sh) RNAs (dE1-RGD/GFP/shMot) and introduced into keloid spheroids for examination of its apoptotic and anti-fibrotic effect. On keloid tissues, mortalin expression was higher than adjacent normal tissues and it's protein expressions were activated keloid fibroblasts (KFs). After primary keloid spheroid were transduced with dE1-RGD/GFP/shMot for knockdown of mortalin, expression of type I, III collagen, fibronectin, and elastin was significantly reduced and transforming growth factor-β1, epidermal growth factor receptor (EGFR), Extracellular Signal-Regulated Kinases 1 and 2 (Erk 1/2), and Smad 2/3 complex protein expression were decreased. In addition, increased TUNEL activities and cytochrome C were observed. Further, for examine of mortalin and p53 interaction, we performed immunofluorescence analysis. Knockdown of mortalin relocated p53 to the cell nucleus in primary keloid spheroids by dE1-RGD/GFP/shMot transduction. These results support the utility of knockdown of mortalin to induce apoptosis and reduce ECMs expression in keloid spheroid, which may be highly beneficial in treating keloids.

Topics: Adenoviridae; Apoptosis; Cell Nucleus; Collagen Type I; Collagen Type III; Elastin; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Fibronectins; Fibrosis; HSP70 Heat-Shock Proteins; Humans; Keloid; Proliferating Cell Nuclear Antigen; Protein Binding; RNA, Small Interfering; Spheroids, Cellular; Transforming Growth Factor beta; Tumor Suppressor Protein p53

We have recently shown that Latent transforming growth factor-beta-1 binding protein-2 (LTBP-2) has a single high-affinity binding site for fibroblast growth factor-2 (FGF-2) and that LTBP-2 blocks FGF-2 induced cell proliferation. Both proteins showed strong co-localisation within keloid skin from a single patient. In the current study, using confocal microscopy, we have investigated the distribution of the two proteins in normal and fibrotic skin samples including normal scar tissue, hypertrophic scars and keloids from multiple patients. Consistently, little staining for either protein was detected in normal adult skin and normal scar samples but extensive co-localisation of the two proteins was observed in multiple examples of hypertrophic scars and keloids. LTBP-2 and FGF-2 were co-localised to fine fibrous elements within the extracellular matrix identified as elastic fibres by immunostaining with anti-fibrillin-1 and anti-elastin antibodies. Furthermore, qPCR analysis of RNA samples from multiple patients confirmed dramatically increased expression of LTBP-2 and FGF-2, similar TGF-beta 1, in hypertrophic scar compared to normal skin and scar tissue. Overall the results suggest that elevated LTBP-2 may bind and sequester FGF-2 on elastic fibres in fibrotic tissues and modulate FGF-2's influence on the repair and healing processes.

Topics: Adolescent; Adult; Binding Sites; Case-Control Studies; Cicatrix, Hypertrophic; Elastic Tissue; Elastin; Extracellular Matrix; Female; Fibrillin-1; Fibrillins; Fibroblast Growth Factor 2; Gene Expression Regulation; Humans; Keloid; Latent TGF-beta Binding Proteins; Male; Microfilament Proteins; Protein Binding; Re-Epithelialization; Signal Transduction; Skin; Transforming Growth Factor beta1

Vitamin C (L-ascorbic acid), a known enhancer of collagen deposition, has also been identified as an inhibitor of elastogenesis.. Present studies explored whether and how the L-ascorbic acid derivative (+) sodium L-ascorbate (SA) would affect production of collagen and elastic fibers in cultures of fibroblasts derived from normal human skin and dermal fat, as well as in explants of normal human skin, stretch-marked skin and keloids.. Effects of SA on the extracellular matrix production were assessed quantitatively by PCR analyses, western blots, biochemical assay of insoluble elastin and by immuno-histochemistry. We also evaluated effects of SA on production of the reactive oxygen species (ROS) and phosphorylation of IGF-I and insulin receptors.. SA, applied in 50-200 μM concentrations, stimulates production of both collagen and elastic fibers in all tested cultures. Moreover, combination of SA with a proline hydroxylase inhibitor induces a beneficial remodelling in explants of dermal scars, resulting in the inhibition of collagen deposition and induction of new elastogenesis. Importantly, we revealed that SA stimulates elastogenesis only after intracellular influx of non-oxidized ascorbate anions (facilitated by the sodium-dependent ascorbate transporter), that causes reduction of intracellular ROS, activation of c-Src tyrosine kinase and the enhancement of IGF-1-induced phosphorylation of the IGF-1 receptor that ultimately triggers elastogenic signalling pathway.. Our results endorse the use of this potent stimulator of collagen and elastin production in the treatment of wrinkled and stretch-marked skin. They also encourage inclusion of SA into therapeutic combinations with collagenogenesis inhibitors to prevent formation of dermal scars and keloids.

Topics: Adult; Ascorbic Acid; Biopsy; Collagen; Elasticity; Elastin; Extracellular Matrix; Female; Fibroblasts; Humans; Insulin-Like Growth Factor I; Keloid; Organ Culture Techniques; Phosphorylation; Prolyl-Hydroxylase Inhibitors; Reactive Oxygen Species; Receptor, IGF Type 1; Regeneration; Skin; Striae Distensae; Tropoelastin

We have shown that the steroid hormone aldosterone, recognized for its action on the kidney and the cardiovascular system, also modulates deposition of extracellular matrix in human skin. We have shown that treatment of primary cultures of normal skin fibroblasts with aldosterone (10 n-1 μM), in addition to stimulation of collagen type I expression, induces elastin gene expression and elastic fiber deposition. We have further shown that the elastogenic effect of aldosterone, which can be enhanced in the presence of mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone, is executed in a MR-independent manner via amplification of IGF-I receptor-mediated signaling. Because aldosterone applied alone stimulates both collagen and elastin deposition in cultures of fibroblasts and in cultures of skin explants derived from dermal stretch marks, we postulate that this steroid should be used in the treatment of damaged skin that loses its volume and elasticity. Moreover, aldosterone applied in conjunction with spironolactone or eplerenone induces matrix remodeling and exclusively enhances elastogenesis in cultures of fibroblasts and explants derived from dermal scars and keloids. We therefore propose that intra-lesional injection of these factors should be considered in therapy for disfiguring dermal lesions and especially in prevention of their recurrence after surgical excision.

Topics: Adult; Aldosterone; Biopsy; Cells, Cultured; Cicatrix; Collagen Type I; Elasticity; Elastin; Eplerenone; Extracellular Matrix; Female; Fibroblasts; Gene Expression; Humans; Keloid; Mineralocorticoid Receptor Antagonists; Organ Culture Techniques; Receptor, IGF Type 1; RNA, Messenger; Skin; Spironolactone; Up-Regulation

Scars are commonly encountered by dermatopathologists and usually do not present a diagnostic challenge. However, in some cases, the pathologist may need to consider a broad differential diagnosis including fibrohistiocytic tumors, smooth muscle tumors, myofibroblastic proliferations and desmoplastic malignant melanoma. Although specific histologic aspects of scars have been well studied, a complete histochemical profile of scars, especially at various stages of evolution, has not been described.. Twenty-five cases of scars including 8 normal scars, 5 hypertrophic scars and 12 keloids were studied. Sections were examined with Verhoeff van Giesson, colloidal iron, Giemsa, smooth muscle actin (SMA), CD34, Factor XIIIa and S-100.. All scars were negative for CD34 expression. Factor XIIIa immunostaining identified only rare dermal dendrocytes. S-100 was absent in 23 of 25 cases and stained scattered cells (less than 10%) in the other 2 cases. SMA was positive in 14 of 25 cases with 6 of these showing staining of up to 50% of spindled cells. Elastic fibers were markedly reduced or absent in all cases, mucin showed moderate or marked staining in three-fourths of the cases and dermal mast cells showed a moderate increase in 5 cases.. These findings confirm prior reports that negative staining with CD34, Factor XIIIa and S-100 can help differentiate scars from dermatofibrosarcoma protuberans, dermatofibroma and desmoplastic malignant melanoma, respectively. SMA staining is much more variable and requires careful interpretation.

Topics: Actins; Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Cicatrix; Elastin; Female; Humans; Hypertrophy; Immunoenzyme Techniques; Keloid; Male; Mast Cells; Middle Aged; Mucins

Topics: Collagen; Collagen Diseases; Connective Tissue Diseases; Elastic Tissue; Elastin; Humans; Keloid; Microbial Collagenase; Neoplasm Invasiveness; Proteoglycans; Wound Healing

Scar tissue, obtained from humans, was stained for elastin fibers by a new staining method. Elastin fibers were noted at sites where they must have been formed de novo. The morphology and the distribution of elastin in various types of scars are described. Practically no elastin was found in keloids.

Topics: Adolescent; Adult; Child, Preschool; Cicatrix; Elastic Tissue; Elastin; Female; Humans; Keloid; Male; Middle Aged; Staining and Labeling