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Insights into the Pathophysiology of Hypertrophic Scars and Keloids: How Do They Differ?

Ghazawi, Feras, M., MD, PhD, MSc; Zargham, Ramin, MD, PhD; Gilardino, Mirko, S., MD, MSc; Sasseville, Denis, MD; Jafarian, Fatemeh, MD

doi: 10.1097/01.ASW.0000527576.27489.0f
Features: Clinical Management Extra

GENERAL PURPOSE: To provide information about the clinical presentation of hypertrophic scars and keloids based on their varied structural components.

TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care.

LEARNING OBJECTIVES/OUTCOMES: After completing this continuing education activity, you should be able to:

  1. Distinguish between the clinical presentations of hypertrophic scars and keloids.
  2. Identify their underlying mechanisms of scarring and the treatments available.

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.

Feras M. Ghazawi, MD, PhD, MSc • Resident Physician • Division of Dermatology • University of Ottawa • Ottawa, Ontario, Canada • Faculty of Medicine • McGill University • Montreal, Quebec, Canada

Ramin Zargham, MD, PhD • Selective Surgical Pathology Fellow • Roswell Park Cancer Institute • Buffalo, New York

Mirko S. Gilardino, MD, MSc • Plastic Surgeon • Division of Plastic and Reconstructive Surgery • McGill University Health Centre • Montreal, Quebec, Canada

Denis Sasseville, MD • Dermatologist • Division of Dermatology • McGill University Health Centre • Montreal, Quebec, Canada

Fatemeh Jafarian, MD • Dermatologist • Division of Dermatology • McGill University Health Centre • Montreal, Quebec, Canada

The authors, faculty, staff, and planners, including spouses/partners (if any), in any position to control the content of this CME activity have disclosed that they have no financial relationships with, or financial interests in, any commercial companies pertaining to this educational activity. This work was partly supported by a research grant from the Canadian Dermatology Foundation.

To earn CME credit, you must read the CME article and complete the quiz online, answering at least 12 of the 17 questions correctly.

This continuing educational activity will expire for physicians on January 31, 2019, and for nurses on January 31, 2020.

All tests are now online only; take the test at http://cme.lww.com for physicians and www.nursingcenter.com for nurses. Complete CE/CME information is on the last page of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.woundcarejournal.com).

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INTRODUCTION

Every year, millions of patients worldwide develop scars after burns, trauma, and surgery. The fibrotic scarring process is initiated following cutaneous injury, which under normal circumstances results in wound closure with a flat scar. In certain circumstances, however, the scar continues to grow, causing pain, pruritus, functional impairment, cosmetic distortion, and psychological distress.

The process of wound healing is dynamic and complex and can be divided into 4 overlapping phases of hemostasis, inflammation, proliferation, and remodeling.1 The process of scarring and wound healing is highly regulated and involves various cells and molecular factors in sequence. Therefore, alterations in any of the wound healing steps can predispose an individual to excessive scarring, which can take different forms, including hypertrophic scars and keloids. Table 1 highlights the characteristics of different scarring types.2–4

Table 1

Table 1

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CLINICAL AND HISTOPATHOLOGIC FEATURES

Keloids and hypertrophic scars can be hard to distinguish from each other clinically.5 They are equally prevalent in both genders, with the highest incidence in the second decade of life.6 Hypertrophic scars usually form 4 to 8 weeks after trauma and are estimated to occur in 40% to 70% of patients following surgery and up to 91% of patients following burn injuries, depending on the wound depth.7 Hypertrophic scars are confined to the wound margin and usually regress within a year. Keloids, on the other hand, grow abnormally beyond wound boundaries and can appear years after skin injury8; they also can form spontaneously without predisposing cutaneous trauma.9,10

The terms hypertrophic scar and keloid were used interchangeably to describe excessive scarring until the histologic distinction between hypertrophic scars and keloids was recognized. Histologically, both hypertrophic scars and keloids are characterized by a thick, highly vascularized dermis that is highly infiltrated with inflammatory cells11 and marked by collagen abundance.7 The epidermal layer is generally normal in both. The reticular layer of the dermis of normal skin consists mainly of fibroblasts and unordered collagen fibers that appear relaxed; injury to this layer is believed to be one of the primary reasons for excessive scarring.3

Hypertrophic scars demonstrate fine, wavy, well-organized, and parallel-oriented collagen fibers and bundles, whereas keloids are characterized by large, thick, wavy, hyalinized collagen fibers and closely arranged collagen bundles.3,11 Keloids also express high levels of both low-density chondroitin sulfate proteoglycans (PGs) and low-density dermatan sulfate PGs, whereas hypertrophic scars express high levels of low-density dermatan sulfate PGs.12

Another difference between hypertrophic scars and keloids is the change in histology over time seen only in hypertrophic scars. Hypertrophic scars in the early stages of maturation (<6 months in duration) are characterized by the presence of many collagenous-cellular nodules that are composed of α-smooth muscle actin (α-SMA)–positive fibroblasts and are fibronectin (FN) positive, whereas in older hypertrophic scars (between 1 and 3 years) the cellular component is inconspicuous and mainly α-SMA negative and FN negative.13 In keloids, however, the histology remains constant irrespective of the scar maturation and composed primarily of α-SMA negative spindle-shaped cells and FN; there are few α-SMA positive and FN positive in prominent collagenous nodules.13,14 Table 2 provides a summary of the unique features of keloids and hypertrophic scars in terms of epidemiology, morphology, symptoms, time course, genetics, histology, and therapeutic potential.

Table 2

Table 2

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EPIDEMIOLOGIC AND GENETIC FEATURES

Strong evidence suggests that genetic factors are involved in the etiology of keloid formation, including common occurrence in twins and siblings15,16 and increased rates of keloid formation in certain populations. Keloids occur in approximately 15% to 20% of patients of African, Hispanic, and Asian descent and much less commonly in whites.2 Keloids apparently do not occur in patients with albinism, indicating that melanocytes play a possible role in keloid formation.17

The predisposition to keloids is an inheritable trait, expressed in an autosomal dominant mode.18–20 Keloid formation has been associated with different alleles of human leukocyte antigen (HLA), namely HLA-DRB1*15, HLA-DQA1*0104, DQ-B1*0501, and DQB1*0503, as well as loci on chromosomes 2q23 and 7p11, among others.21,22 Further, several single-nucleotide polymorphisms that are associated with keloid formation were identified in the Chinese Han population.23 The roles of gene loci in the context of keloids formation are detailed elsewhere by Shih and Bayat.21

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MOLECULAR MECHANISMS AND FACTORS

The pathophysiology of hypertrophic scars and keloids can be addressed with 4 major categories that intersect at many levels of wound healing: proliferation, inflammation, extracellular matrix (ECM) formation, and other factors. Table 3 and the Figure (Supplemental Digital Content 1, http://links.lww.com/NSW/A11) summarize and compare the different factors involved in the pathogenesis of hypertrophic scars and keloids.

Table 3

Table 3

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Proliferation

Perhaps not surprisingly, the proliferative capacity of fibroblasts from hypertrophic scars is greater than that of normal skin.24 However, compared with normal skin and hypertrophic scars, keloid fibroblasts possess higher proliferating cell nuclear antigen expression and display apoptosis resistance.25,26 This indicates that keloids form as a result of an abnormal wound-healing process with a prolonged proliferative phase because of an apoptosis-resistant phenotype that in turn allows a state of continued production of excessive collagen beyond the amount expected in normal scar or cicatrix formation. It is likely that the formation of aberrant scarring is mediated through a combination of enhanced proliferation and collagen production capacity as well as apoptosis resistance, among other molecular factors that can be implicated in the process.

Although hypertrophic scars and keloids share common anomalies in some apoptotic gene expression, they differ in others. Their different apoptotic-resistance profiles may account for their different manifestations. The level of the tumor suppressor p53 protein found in fibroblasts isolated from hypertrophic scars is significantly higher than in normal and keloid fibroblasts, and keloid fibroblasts possess mutations in exons 5, 6, and 7, whereas hypertrophic scars possess mutations in exon 7.27 Further, fibroblasts derived from keloids are significantly resistant to Fas-mediated apoptosis.28

It is likely that the delay of apoptosis of resistant fibroblasts in keloids may account for the uncontrolled production of large amounts of collagen.29 In fact, the expression of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) was quantified by immunohistochemical methods in normal skin and different scar tissues, and it was found that the expression rate of Bcl-2 protein in both hypertrophic scar fibroblasts and keloid fibroblasts was higher than in normal skin; however, it was significantly higher in keloids than in hypertrophic scars.30 Further, levels of Bcl-2 proteins in peripheral blood mononuclear cell fractions of burn patients with hypertrophic scars were quantified by enzyme-linked immunosorbent assay.31 These fractions expressed significantly higher levels of Bcl-2 proteins compared with peripheral blood mononuclear cell fractions from a control cohort. These data suggest that increased levels of Bcl-2 proteins may be implicated in the pathogenesis of hypertrophic scarring by delaying fibroblast apoptosis.31 However, increased activated caspases 3 and 9 and apoptosis were reported in keloid fibroblasts compared with hypertrophic scar and normal skin fibroblasts.32 In addition, Lee et al33 found that Bcl-2 levels were decreased in keloid tissues, leading to apoptotic dysregulation. The differences in Bcl-2 expression trends that are reported by different studies can be explained, at least in part, by findings from a study by Ladin et al34, where the apoptotic rates and expression levels of Bcl-2 and Fas protein levels were measured and compared between fibroblasts extracted from both the hypocellular central regions and hypercellular peripheral regions of keloid scars. The study found that the hypercellular peripheral regions and those immediately below the epidermis of keloid scars had high Bcl-2 expression, consistent with increased proliferation in the newer expanding regions of the scar. This was in contrast with hypocellular central, deep dermal, and older areas of the keloids, which showed the opposite trend (high expression of Fas antigen and low Bcl-2 levels) consistent with increased apoptotic rate, likely as a control mechanism to regulate scar growth.34 Therefore, impairment in the fine regulation of apoptosis contributes to abnormal scarring, and this occurs even within different sites in scar tissues. More research is needed to determine precise factors regulating apoptosis in the abnormal scarring.

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Inflammation

An impaired inflammatory response to skin injury is implicated in the development of hypertrophic scars and keloids.7,35 The type of immune response is an important modulator of fibrogenesis, in which a type 1 T-helper cell (TH1) response attenuates skin fibrosis through secretion of interleukin 12 (IL-12) and interferon γ,36 whereas a TH2 response has been strongly linked to fibrogenesis.7 Consistently, TH2 cytokines secreted by CD4+ T cells such as IL-4, IL-5, IL-10, and IL-13 have been implicated in the development of keloids.7

Both the intensity and the type of the immune response significantly contribute to abnormal scar formation. In fact, the dermis in both keloids and hypertrophic scars is infiltrated by CD3+, CD45RO+, and HLA-antigen D–related CD4+ T cells, as well as CD1a+/CD36+/intercellular adhesion molecule–positive dendritic cells.13 However, in hypertrophic scars, the amount of infiltrate is variable with the age of the scar (proportional with severity), and it is extremely elevated and insignificantly variable with age in keloids.13 Collectively, it is likely that the infiltration by immune cells contributes to excessive scarring, and consistent presence of these immune cells contributes to keloid formation.

Aberrant cytokine secretion from chronic infiltration of immune cells in keloids significantly contributes to the development of pathogenic scars.13 Several cytokines are dysregulated in keloids and hypertrophic scars, such as IL-1β,37 tumor necrosis factor α,38 vascular endothelial growth factor, connective tissue growth factor, platelet-derived growth factor, and particularly transforming growth factor β (TGF-β).39,40 Transforming growth factor β is the principal stimulator of collagen production and is overexpressed in keloids and hypertrophic scars.41 There are 5 conserved isoforms of TGF-β, with β1 to β3 being the principal mammalian forms.7 Transforming growth factor β1 and TGF-β2 stimulate the synthesis of collagen and PGs, whereas TGF-β3 plays key roles in decreasing the deposition of connective tissue.7 Therefore, it is not surprising that inhibiting the activity of TGF-β1 by injecting animals with neutralizing antibodies to TGF-β1 resulted in decreased fibrosis and deposition of scar tissue.42

The mRNA expression of TGF-β1, TGF-β2, and TGF-β3 and their receptors I and II in hypertrophic scars, keloids, and normal skin was measured in dermal fibroblasts from freshly taken skin biopsies and confirmed that the levels of the 3 isoforms of TGF-β were dysregulated in the aberrant scarring disorders compared with normal skin. However, comparing hypertrophic scars with keloids, there were significantly less TGF-β1 and TGF-β2 and more TGF-β3 mRNA in hypertrophic scars.43 Further, the ratio of TGF-β receptor I (TGF-βRI) to TGF-βRII in keloid fibroblasts was higher compared with hypertrophic scarring,43 and the increased ratio of TGF-βRI to TGF-βRII was reported in another study to promote collagen synthesis.44 Ultimately, the differences in TGF-β isoforms and receptors expression could at least partially account for the onset of either disorder.

The anti-inflammatory cytokine IL-10 attenuates the inflammatory response following an inflammatory process such as skin injury.45 The attenuation by IL-10 is mediated through several mechanisms, including down-regulation of the profibrotic cytokines IL-6 and IL-846,47 and inhibition of the key regulator of inflammation, the transcription factor nuclear factor B.48,49 The mechanisms by which IL-10 modulates antifibrotic effects have been an important focus of research, particularly in the past decade, for potential therapeutic application against aberrant scarring. In fact, IL-10 was administered in an animal model 3 days before wounding, and compared with the control group, the wounds of IL-10–treated animals had lower levels of proinflammatory mediators and demonstrated normal collagen deposition and normal dermal architecture.50 More recently, IL-10 was demonstrated to promote regenerative healing and improve dermal architecture by mediating antifibrosis in skin scarring.51 It is still not completely understood whether there are significant differences in the levels of IL-10 and IL-10 receptors in keloids and hypertrophic scars. More research is required to optimize IL-10 therapy for pathologic scarring.

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Extracellular Matrix

Extracellular matrix is the noncellular component of all tissues and organs and plays pivotal roles in the structural and biochemical support of the tissue and facilitates cell-to-cell communication. The 2 primary macromolecule constituents of the ECM are PGs, such as chondroitin sulfate, heparan sulfate, and keratan sulfate, and fibrous proteins, including FN, collagen, elastin, and laminin. It is not surprising that components of the ECM are implicated both in aberrant wound healing processes and in explaining the differences between keloids and hypertrophic scarring.52

Fibronectin. Fibroblasts are the principal cells of scar tissue and are responsible for the synthesis of matrix proteins that are involved in the remodeling process.2 Fibronectin, a product of fibroblasts, is a key glycoprotein constituent of the ECM that binds to the membrane-spanning receptor proteins integrins, as well as other components including collagen and fibrin.53 The expression of FN is tightly regulated during wound healing. In the early stage of wound healing, there is an increased availability of FN with low expression of collagen fibers, and this trend reverses in the maturation and remodeling phase of wound healing.54,55

Levels of FN are significantly higher in hypertrophic scars and keloids compared with normal skin.56 The overproduction of FN in hypertrophic scars and keloids suggests a dysregulated healing process. In fact, as already discussed, TGF-β1 levels are augmented in hypertrophic scars and keloids, and 1 of the downstream effects of such an increase is a significant increase in the biosynthesis of FN and ECM.54 The distribution of FN is different between the 2 different types of scars. In hypertrophic scars, FN is dispersed diffusely throughout the dermis in a linear or curling arrangement,57 but in keloids FN is localized in high density in the intercellular matrix.58

Integrin. Fibroblasts interact with other cells in the ECM through integrin proteins that function as bridges for cell-to-cell communication.59 In response to skin injury, integrin proteins facilitate the binding of their ligand collagen to matrix metalloproteinases (MMPs), which in turn re-epithelialize the wound and help to form a scar.60

Integrins are composed of 1α and 1β subunit. There are 18 α and 8 β subunits in mammals,61 and various combinations of these subunits produce different integrin proteins, each with their own signaling properties.62 It is likely that different integrins recruit different signaling molecules and differentially control cell signaling and cellular tension.63

The integrins α1β1, α2β1, and α3β1 bind to laminin, collagen, FN, and other ECM components.64 In fibroblasts, collagen is recognized by α1β1 and α2β1 integrins that regulate collagen synthesis through a negative feedback mechanism.2 Consistently, neutralizing antibodies against α1ß1 integrin proteins block the down-regulation of collagen synthesis.65

Integrin expression is influenced by cytokines such as TGF-β1 that significantly up-regulate its expression,54 so it is not surprising that integrin expression is affected in hypertrophic scars and keloids. In fact, expression of α1β1 integrin is significantly increased in keloidal fibroblasts, and increased but to a lesser extent in hypertrophic scars, compared with normal skin.66 The collagen-binding α2β1 integrin is the most abundant collagen receptor on the surface of keratinocytes that reside primarily in the stratum basale layer of the epidermis.67 The α2β1-integrin mRNA, which mediates several processes including wound healing,68 was quantified in keloids, hypertrophic scars, and normal skin.69 The α2β1-integrin mRNA expression was significantly augmented in fibroblasts from hypertrophic scars and keloids compared with normal skin, and protein expression was significantly higher in keloids than in hypertrophic scars.69

Matrix metalloproteinases. Matrix metalloproteinases are endopeptidases with the primary function of degrading an array of ECM proteins.70 Along with serine proteinases such as tissue plasminogen activator and urokinase plasminogen activator, MMPs counteract fibroblast production of ECM proteins and provide a balance by preventing excessive matrix synthesis.

The degradation of collagen types I, II, and III is mediated by MMP-1 (collagenase 1), MMP-8 (collagenase 2), and MMP-13, respectively.2 The activity and function of MMPs are also dependent on several factors that are dysregulated in aberrant scarring pathologies such as hypertrophic scarring and keloids. For instance, the expression of MMPs is regulated at least in part by TGF-β, so it is not surprising that expression of the different isoforms of MMP is affected in keloids and hypertrophic scars. In fact, compared with normal skin, the mRNA and protein expression are significantly higher for MMP-13 and lower for MMP-1 and MMP-8 in keloids.71

Potential differences in the expression of all MMP isoforms between hypertrophic scars and keloids are yet to be completely elucidated. Collectively, while excessive collagen synthesis plays a role in excessive scar formation, a reduced breakdown of collagen because of the dysregulation of proteinases such as MMP-1 and MMP-8 may also contribute to the pathology.

Fibrillin 1 and elastin. These components of the ECM allow tissue to resist tensile or stretching forces. The major components of elastic fibers are elastin and fibrillin-rich microfibrils.72 The distribution of elastin and fibrillin 1 is reduced in normal scars and more significantly in both hypertrophic scars and keloids.73 Although the expression of fibrillin 1 is reduced in both types of scars in comparison with normal skin, there are no significant differences in fibrillin 1 expression between hypertrophic scars and keloids in either the superficial or deep dermis. Elastin levels, however, are reduced in both hypertrophic scars and keloids compared with normal skin in superficial dermis, but in deep dermis, elastin levels are reduced only in hypertrophic scars and actually significantly increased in keloids.73 The disruption of elastic system components likely contributes to the distinct biomechanical properties of hypertrophic scars and keloids.73

Collagen. Collagen proteins, secreted by fibroblasts, are the most abundant fibrous protein within the interstitial ECM, and through their association with elastin, they provide tensile strength and regulate cellular development, adhesion, and migration.74,75 Collagen deposition is a key determinant for scar formation, particularly in the case of hypertrophic scars and keloids where collagen types I and III are thought to account for the excessive scarring.8 While collagen expression is increased in both hypertrophic scars and keloids compared with normal skin, the ratio of type I to type III collagen is significantly increased in keloids compared with hypertrophic scars (approximately 17:1) and with normal skin.76 Conversely, collagen III/I expression is significantly higher in hypertrophic scars (approximately 6:1) compared with keloids.77 The differential expression of collagens may allow the distinction between the 2 entities through immunohistochemistry and confocal microscopy.77

Connexin. Gap junctions are organized aggregates of protein channels in cell membranes that serve as passageways to adjacent cells and allow for communication and exchange of proteins, ions, and other signaling molecules.78 The core constituents of gap junctions are the connexin proteins.78 Connexin proteins play important roles in the intercellular communication between fibroblasts and other cell types, and dysregulation of connexin expression has been implicated in tumorigenesis.79 In fact, connexin-43 expression and gap junctional intercellular communication are reduced in keloid and hypertrophic tissues compared with normal skin, and keloids had significantly lower connexin-43 expression than hypertrophic scars.80 It has been postulated that because of the reduced gap-junctional intercellular communication in hypertrophic scars and keloids, fibroblasts do not receive sufficient inhibitory and apoptotic signals from adjacent cells, and this partially accounts for the abnormal proliferation in these scars.80 In fact, gap junctions play important roles in modulating intercellular communications and dynamic reciprocity among fibroblasts and mast cells as demonstrated by the knockdown of connexin-43 in both, which blocked transformation of fibroblasts into α-SMA–expressing myofibroblasts.81

Decorin. Decorin is a small dermal ECM PG that plays important roles in regulating the assembly and organization of the ECM by binding to several components such as collagen and FN.82 Decorin expression in hypertrophic scars is reduced by approximately 75%.83 Consistently, the measurement of decorin in burn wounds at various stages of healing has revealed that its expression is decreased in hypertrophic scarring and that levels recover as hypertrophic scarring resolves.84 Similarly, decorin expression is also dysregulated in keloids.85 In fact, recombinant human decorin down-regulates TGF-β1 production and induces growth suppression in keloid fibroblasts, suggesting its therapeutic potential as an antifibrotic agent.86 Aberrant expression of decorin and other small leucine-rich PGs likely contributes to the altered physical properties of hypertrophic scars and keloids, and proper scar healing may depend on appropriate expression of PGs.83

Hyaluronan. Hyaluronan is a high-molecular-mass glycosaminoglycan (polysaccharide) component of the ECM that plays pivotal roles in cell proliferation and migration.87 It is active in the proliferative phase of wound closure and scar formation. Hyaluronan levels increase quickly following skin injury to orchestrate the appearance and maintenance of myofibroblasts, and then degrades in a highly regulated process involving hyaluronidases and reactive oxygen species (ROS).87 Hyaluronan levels are abnormally decreased in aberrant scars, suggesting a regulatory role of hyaluronan in mediating normal wound closure and scar formation.87–89 Hyaluronan expression is regulated by TGF-β–mediated proliferation of fibroblasts, and therefore alterations in TGF-β levels and subsequent variation in hyaluronan expression may contribute to the development of either hypertrophic scars or keloids.90 In hypertrophic scars, hyaluronan is distributed mainly in the papillary dermis, similar to normal skin and indicating a better capacity to recover like normal skin over time, whereas keloids lack the accumulation of hyaluronan in the papillary dermis, and hyaluronan is mainly distributed in the reticular layer.89

Dermatopontin. A noncollagenous component of the ECM, dermatopontin binds small dermatan sulfate PGs, decorin, and collagens; is involved in modification of collagen fibrillogenesis; and promotes cell adhesion by integrin binding.91 Decreased expression of dermatopontin is associated with abnormal scarring. In fact, fibroblasts from hypertrophic scars show a 2- to 3-fold reduction of dermatopontin mRNA and protein compared with fibroblasts from normal skin.92 Keloid fibroblasts express low levels of dermatopontin.93 Exogenous treatment of fibroblasts in vitro with TGF-β1 increased dermatopontin mRNA expression, whereas IL-4 treatment reduced dermatopontin mRNA expression compared with untreated samples.92 Therefore, it is likely that altered levels of TGF-β, and consequently dermatopontin, contribute to the pathogenesis of hypertrophic scarring and keloid formation.

Periostin. This ECM protein is involved in tissue remodeling by promoting the differentiation and activation of fibroblasts.94 Levels of periostin typically increase a few days following wound repair, peaking after 7 days and decreasing thereafter.94 Periostin is significantly induced by TGF-β1 in vitro.95 Perhaps not surprisingly, the expression of periostin is increased in hypertrophic scars and keloids compared with normal skin.95 The mRNA expression of periostin, however, is higher in keloids than in hypertrophic scars,96 highlighting periostin as an additional contributing factor in keloid formation.

Tenascin. Tenascins are multifunctional ECM glycoproteins expressed during fetal development and in wound repair but very limited in adult tissue, which modulate cellular adhesion through antagonizing cell attachment to FN. They play a critical role in initiating keratinocyte and fibroblast migration to wound sites.97 Tenascin proteins are present at wound margins within 4 and 24 hours after injury in fetal and adult skin tissue, respectively, consistent with their role in the rapid epithelialization seen in wound healing.98 There appears to be differential tenascin expression in different scar tissue. There are no significant differences in tenascin protein levels in fibroblasts from hypertrophic scars and normal scars.99 However, tenascin C expression levels are significantly higher in keloids compared with normal scars and skin.100 Further, the distribution of tenascin C is different in keloid tissue; it infiltrates the reticular and papillary dermis, whereas in normal skin tenascin is restricted to the dermal-epidermal junction in the superficial papillary dermis.100

Laminin. This integral glycoprotein component of the basal lamina mediates cell adhesion by binding to several cell surface receptors and other ECM molecules.101 It is only recently that an understanding of its role in angiogenesis, scar formation, and wound repair has emerged.102 No significant differences were found in the protein expression of laminin in fibroblasts from hypertrophic scars compared with normal scars over a 1-year period.99 However, laminin β2 protein expression is significantly increased in keloid fibroblastic cell lines compared with normal fibroblasts.103

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Other Factors

Mast cells. There is a significant elevation in the number of mast cells in hypertrophic scars compared with mature scars and normal skin.104–107 Similarly, the number of mast cells in keloids is significantly increased.108 The activation of mast cells results in the release of several fibrogenic mediators such as histamine that mediate collagen fiber synthesis, tryptase (which stimulates the synthesis of type I collagen), and chymase (a protease that cleaves procollagens, aids in fibril synthesis, and contributes to scar formation).29 Further evidence of the roles of mast cells in aberrant scar formation comes from experiments where the skin of pigs that are prone to hypertrophic scarring after wounding had reduced collagen fiber deposition and scarring when treated with ketotifen, a second-generation noncompetitive H1-antihistamine and mast cell stabilizer.109 More research is needed to fully elucidate differences in mast cell activation between the 2 pathologic scarring entities discussed in this article.

Cyclooxygenases. Prostaglandins are metabolites of arachidonic acid produced by the catalytic action of cyclooxygenase 1 (COX-1) and COX-2.110 In normal skin, COX-1 is localized throughout the epidermis, and COX-2 is present predominantly in suprabasal keratinocytes.111 A significant up-regulation of COX-1 protein exists in hypertrophic scars compared with keloids and normal skin, and in keloids there is significant up-regulation of the COX-2 protein, highlighting the distinct pathophysiology of both entities.112 Further, COX-2 has been detected in lymphocytes and macrophages from keloid tissue, suggesting that inflammatory cells may also contribute to the development of keloids by COX-2 expression.110 The expression of COX-1 is induced by TGF-β, whereas COX-2 is induced by tumor necrosis factor α.113 This suggests that different cytokine milieus and inflammatory cells may influence the expression of each COX and predispose the scar to develop a specific form of aberrant scarring.

Heat shock proteins. Heat shock proteins (HSPs) function as molecular chaperones to stabilize new protein synthesis and are involved in posttranslational modification processes to ensure correct folding.114 These HSPs are involved in the synthesis of ECM proteins: for instance, HSP47 is a collagen-specific factor that stabilizes procollagen during protein synthesis and ensures proper folding of the protein.115 Irregular HSP expression is implicated in abnormal wound healing.116 In fact, in keloids, compared with normal skin, there is a significant overexpression of HSP27, HSP47, and HSP70 and no differences in HSP60 and HSP90 protein expression, indicating that the dysregulation of specific members of HSPs may be implicated in keloid scar formation.117 Several studies69,118,119 reveal interesting findings that may implicate the differential expression of HSPs in the pathogenesis of hypertrophic scars and keloids, and more research is needed to fully elucidate the roles of each HSP in these disorders.

Calcitonin gene-related peptide and plasminogen activator inhibitors. Recently, the mRNA and protein expression levels of 2 other genes, calcitonin gene-related peptide and plasminogen activator inhibitor 2 (PAI-2), were found to be elevated in keloids compared with hypertrophic scars and normal skin.69 These genes are implicated in wound healing, and their overexpression could contribute to the pathology seen in aberrant scars.120–122 Elevated levels of PAI-1 play an important role in a decreased capacity for fibrinolysis and excessive collagen accumulation in keloids.123–125 Recently, elevated levels of PAI-1 were also reported in hypertrophic scar–derived fibroblasts as compared with normal skin.126 More studies that compare the differential expression of PAIs and calcitonin gene-related peptide may reveal important differences that may contribute to keloid and hypertrophic scarring pathogenesis.

Reactive oxygen species, nuclear factor erythroid 2–related factor 2, and nitric oxide. Elevated levels of ROS have been implicated in many fibrotic disorders, including fibrotic skin diseases. In fact, elevated levels of ROS were reported in both keloid and hypertrophic scar fibroblasts, compared with normal fibroblasts, with higher levels in hypertrophic scars than keloids.27

A key transcription factor, nuclear factor erythroid 2 (Nrf2), regulates the expression of many genes, including those involved in apoptosis and in the mediation of the protective cellular response against oxidative stress, triggered by different processes including inflammation and injury.127 Indeed, in comparison with normal skin tissue, keloid tissues are associated with significantly elevated levels of oxidative stress.33 Consistently, levels of Nrf2 in keloid tissue were significantly lower than in normal skin.33 Currently, possible roles of Nrf2 in the formation of hypertrophic scars are still to be investigated.

Nitric oxide is one of the few recognized gaseous signaling molecules (gasotransmitters) and a mediator of a wide array of physiologic and pathologic processes.128,129 It is produced by nitric oxide synthase (NOS). There are 3 human isoforms of NOS, the inducible NOS (iNOS), and 2 constitutive Ca2+-responsive NOS (cNOS).130 Nitric oxide plays a role in wound remodeling by mediating keratinocyte proliferation and modulating collagen synthesis in fibroblasts.131 Elevated levels of iNOS mRNA and proteins were detected in keloid tissues compared with normal skin tissue controls, although cNOS was not examined in the study.132 Further, exposure of keloid fibroblasts to exogenous nitric oxide resulted in up-regulation of type I collagen synthesis, confirming the functional relevance of iNOS in regulating collagen synthesis in keloid scars.132 On the other hand, the expression of iNOS is not altered in hypertrophic scar fibroblasts.133 However, dermal fibroblasts derived from hypertrophic scar tissue were shown to express lower levels of cNOS and produce less nitric oxide than normal fibroblasts.133 It is likely that contributions of different NOS isoforms contribute to the pathogenesis of aberrant scar formation, and more research in this avenue could help to better delineate the mechanisms of keloids versus hypertrophic scars.

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TREATMENT

There are a number of available surgical options as well as topical, oral, and systemic therapies for aberrant scarring. However, research has not yet defined a cure for keloids and hypertrophic scars, and the search for one further highlights the current knowledge deficit around the molecular mechanisms underlying these disorders. The available therapeutic modalities include silicone gel sheeting, compression therapy, surgical excision followed by radiation therapy, occlusive dressings, intralesional corticosteroid injections, cryotherapy, laser therapy, and interferon therapy, among others. Detailed reviews on the available treatments modalities of hypertrophic scarring and keloids are discussed in the following references.4,7,134–136 It is important to note that currently most of the indicated therapeutic modalities are generally used for both aberrant scarring entities.7 Therefore, better understanding of the pathophysiology of hypertrophic scars and keloids will allow for the development of specific and targeted therapies for each condition.137–138

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CONCLUSIONS

Numerous pathophysiologic and clinical factors are implicated in the pathogenesis of aberrant scars, hypertrophic scars, and keloids. Researchers and clinicians should strive to identify and understand the specific causal mechanisms in the pathogenesis of hypertrophic scars and keloids. This knowledge will potentially help in developing specific and effective therapeutic modalities and better treatment outcomes.

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PRACTICE PEARLS

  • Millions of patients each year develop hypertrophic scars and keloids following trauma or surgery. They result from pathologic wound healing and often cause pain, dysfunction, and decreased quality of life.
  • There are important differences between hypertrophic scars and keloids in terms of clinical presentation, epidemiology, and histologic findings.
  • The underlying molecular mechanisms and factors of keloids and hypertrophic scarring are distinct and unique to each.
  • Current treatment options remain incompletely effective, most likely because of a lack of understanding of the pathophysiology of the different types of aberrant scars.
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Keywords:

aberrant scarring; collagen; elastin; fibrillin 1; hypertrophic scars; keloids; TGF-β

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