[Academic Presentation] Research on the Pathogenesis of Keloids

Article reprinted from: Chinese Journal of Dermatology and Venereology

Authors: Zhu Lianhua, Li Meiling, Li Zhouna, Kim Chol-ho

Keloids are benign neoplasms that arise from an imbalance between collagen and extracellular matrix synthesis and degradation following tissue injury, resulting in excessive collagen deposition. They exhibit infiltrative growth into the dermis and subcutaneous tissues, typically do not regress spontaneously, and display a degree of genetic predisposition, arising from the combined effects of multiple genes. After extensive research, scholars have identified cytokines and genes implicated in the pathogenesis of keloids and have elucidated the roles of various genes and cytokines in the onset and progression of keloids, as well as the mechanisms underlying their interactions. This review summarizes the latest advances in our understanding of the pathogenic mechanisms of keloids.

1 cytokine

1. 1 Transforming growth factor-β (TGF-β) TGF-β is a secreted polypeptide signaling factor that exists in mammals as three isoforms: TGF‑β1, TGF‑β2, and TGF‑β3. TGF‑β stimulates the synthesis and deposition of extracellular matrix proteins, inhibits the production of collagenase, and counteracts the mitogenic effects of certain cytokines; it also serves as an effective chemoattractant for fibroblasts. Through paracrine and autocrine mechanisms, it acts on inflammatory and reparative cells, exerting critical biological functions such as promoting chemotactic migration, proliferation, differentiation, and the synthesis and secretion of extracellular matrix components. TGF‑β1 primarily mediates extracellular matrix synthesis and cell migration, whereas TGF‑β2 mainly regulates cell growth and proliferation, enhancing the secretion of extracellular matrix proteins like fibronectin and collagen. In the TGF‑β1/Smad3 signaling pathway, TβR‑I plays the central role in signal transduction; this pathway comprises two serine/threonine kinase receptors and Smad proteins that can translocate into the nucleus. Receptor‑bound Smad7 functions as a negative feedback regulator of the TGF‑β1/Smad3 signaling cascade; in keloid tissue, downregulation of Smad7 mRNA levels leads to impaired negative feedback inhibition within this pathway.

1. Fibroblast growth factor (FGF) FGF is a family of proteins. On the one hand, FGF promotes fibroblast proliferation; on the other hand, it stimulates the expression of collagenase. It not only facilitates fibroblast mitosis and mesenchymal cell growth but also induces angiogenesis, playing a crucial role in wound healing. Fibroblast growth factors include acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF). aFGF, which inhibits type I collagen, exhibits a proliferative effect on both hypertrophic scar and normal skin fibroblasts cultured in vitro, with the pro‑proliferative effect intensifying as its concentration increases. Moreover, aFGF strongly stimulates the proliferation of vascular endothelial cells and can chemotactically recruit these cells into the collagen matrix. Given bFGF’s potent mitogenic activity on vascular endothelial cells, it likewise promotes angiogenesis. In addition, bFGF markedly downregulates the mRNA expression of type I collagen in hypertrophic scars and keloids, thereby reducing collagen synthesis, while simultaneously upregulating collagenase mRNA levels, enhancing collagenase expression, and increasing its enzymatic activity.

1. 3 Vascular endothelial growth factor (VEGF) VEGF is a glycoprotein synthesized and secreted by various normal cells and tumor cells. It is predominantly expressed in the basal and spinous layers of the epidermis and in the cytoplasm of vascular endothelial cells, playing a critical role in angiogenesis, wound healing and tissue repair, as well as tissue regeneration. Upon binding to its receptor, VEGF promotes the recruitment of inflammatory cells, stimulates the proliferation of vascular endothelial cells, and increases microvascular permeability to macromolecules, thereby exacerbating the inflammatory response. In normal skin, VEGF is expressed at low levels, whereas it is overexpressed in myofibroblasts within the infiltrative areas of keloids. VEGF can upregulate the expression of plasminogen activator inhibitor‑1, while having no significant effect on normal skin fibroblasts. Furthermore, it does not stimulate urokinase‑type plasminogen activator either in normal skin or in keloid tissue, and evidence indicates that the extracellular signal‑regulated kinase signaling pathway also contributes to VEGF‑induced upregulation of plasminogen activator inhibitor‑1.

1. 4 Platelet-derived growth factor (PDGF) PDGF is a potent mitogen for cells of mesenchymal origin, primarily released from α‑granules of platelets; it is also produced by vascular endothelial cells, activated macrophages, and vascular smooth muscle cells, driving cells rapidly into S phase. Collagen and fibronectin are abnormally synthesized in the extracellular matrix as a result of PDGF‑induced macrophage activation and subsequent fibroblast proliferation. Following tissue injury, PDGF is among the first growth factors to reach the wound site, participating in wound healing while regulating collagen synthesis and degradation—processes mediated largely through PDGF’s effects on fibroblast proliferation, division, chemotaxis, and increased fibronectin production. In keloid tissues, fibroblasts exhibit upregulation of PDGF receptor α at the transcriptional level, leading to elevated protein expression. Although PDGF receptor β expression is also increased, its protein is predominantly localized to the nucleus rather than the cell membrane. Consequently, the pro‑inflammatory and keloid‑promoting effects are chiefly attributable to PDGF receptor β on the surface of keloid fibroblasts.

2 genes

2. Human Runt-related transcription factor 3 (RUNX3) RUNX3

The RUNX3 gene is a newly identified tumor suppressor gene and an important member of the Runt‑related transcription factor family. It is located on the short arm of human chromosome 1, at 1p36.1, with a total length of approximately 67 kb, comprising six exons and an open reading frame of 1,290 bp. Methylation of a highly conserved, typical CpG island region is the primary mechanism underlying the inactivation of RUNX3 expression. The RUNX3 gene may serve as a critical component in the TGF‑β signaling pathway, participating in the negative regulation of epithelial cell growth mediated by TGF‑β. In keloid tissue, excessive fibroblast proliferation results from the loss or silencing of the RUNX3 gene. A specific mutation within the RUNX3 gene—specifically, the RH120480 fragment—is unique to keloid lesions, leading to an impaired response of fibroblasts to the negative regulatory effects of TGF‑β. Consequently, TGF‑β promotes both fibroblast expansion and extracellular matrix accumulation, triggering uncontrolled collagen deposition, disrupting the balance between cell proliferation and apoptosis, and driving a large proportion of fibroblasts into the proliferative phase, thereby contributing to the hypertrophic and infiltrative growth characteristic of keloid tissue.

2. 2 P53 gene The P53 gene is an important regulator of the cell cycle and apoptosis, serving as a suppressor of cell growth. In keloids, mutations in the P53 gene can give rise to truncated or unstable P53 proteins. The P53 protein encoded by the P53 gene…

Protein can regulate normal cell apoptosis and proliferation, maintain genomic integrity, control the cell cycle, and induce cell differentiation and apoptosis. Mutations, except those in exon 4, are all located within the P53 protein’s specific DNA-binding domain, thereby impairing its ability to bind to target DNA sequences. In contrast, mutations outside the DNA-binding domain can alter the three-dimensional conformation of the p53 protein and disrupt its phosphorylation, leading to loss of normal transcriptional activation and abolishing its inhibitory effect on cell proliferation, thus manifesting a dominant-negative effect. Alterations in the structure of the P53 gene can attenuate fibroblast apoptosis, promote sustained fibroblast proliferation, and result in excessive collagen accumulation. Foreign researchers have found that Np63 is highly expressed only in keloid fibroblasts, and its overexpression can inhibit P53 activity.

2. 3 Fas gene Fas‑mediated apoptosis plays a crucial role in the apoptosis of fibroblasts. The Fas genomic DNA is located on chromosome 10q24 and spans 36 kb. As a member of the nerve growth factor (NGF)/tumor necrosis factor (TNF) receptor family, Fas‑dependent death signaling represents one of the primary pathways driving apoptosis in pathological scar‑forming fibroblasts. Mutations in exons 6, 8, and 9 can lead to either complete loss of Fas protein expression or production of a nonfunctional protein, resulting in defective fibroblast apoptosis and excessive proliferation, which ultimately contributes to the development of hypertrophic scars. The degree of glycosylation of Fas protein varies significantly: fibroblasts from hypertrophic scars exhibit the highest level of Fas glycosylation, followed by those from keloids, with healthy skin showing the lowest. Dysregulation of Fas‑mediated apoptosis by the Fas gene promotes uncontrolled fibroblast proliferation, thereby giving rise to keloid formation. Furthermore, the binding of Fas protein to Fas ligand activates apoptotic effector molecules, triggering rapid apoptosis in cells expressing Fas L.

2. 4 Smads genes (drosophila mothers against decapentaplegic protein, Smads) Dysregulated expression of Smad genes can lead to delayed wound healing, non‑healing wounds, or excessive scar formation. The Smad3 gene, a member of the Smad gene family, is located at 15q21–22 and has a full length of approximately 5.7 kb. Activation of receptor‑bound Smad3 serves as an intermediate step in the signaling cascade; following Smad3 expression, TGF‑β fails to induce type I collagen synthesis. Observations indicate that local downregulation of Smad3 and upregulation of Smad7 in the wound environment effectively block the TGF‑β1/Smad3 signaling pathway, thereby reducing extracellular matrix deposition. TGF‑β1 is a potent chemoattractant for fibroblasts, acting—via paracrine and autocrine mechanisms—directly or indirectly, either alone or in concert, and either simultaneously or sequentially, on inflammatory and reparative cells. It elicits three key biological effects: chemotactic migration, cellular proliferation and differentiation, and the synthesis and secretion of extracellular matrix. The TGF‑β1/Smad3 signaling pathway influences every stage of scar formation and maturation. It is not expressed during infancy but exhibits variable expression levels across different phases of human growth and development; effectively inhibiting the TGF‑β1/Smad3 signaling pathway can reduce extracellular matrix deposition.

2. Collagen triple helix repeat containing 1 (Cthrc1) Cthrc1

Genes were first identified in studies examining sequence differences between normal aortic tissue and injured arterial tissue. Cthrc1 is expressed in damaged or diseased arteries, where it suppresses collagen expression and cell migration, thereby modulating the scar‑formation process. Cthrc1 is a novel gene product with biochemical activity; as a potent regulator of collagen matrix deposition, it exerts its effects through interactions with the TGF‑β signaling pathway. In keloid fibroblasts, overexpression of Cthrc1 markedly inhibits TGF‑β1‑induced expression and synthesis of type I collagen. 2.6 PTEN Gene The PTEN gene is a tumor suppressor that exhibits phosphatase activity. The protein encoded by PTEN displays dual specificity in the cytoplasm. By virtue of its lipid phosphatase and protein phosphatase activities, PTEN regulates cell motility, adhesion, growth, and migration. Under certain pathological conditions, PTEN expression declines during tissue repair, leading to uncontrolled fibroblast proliferation, disordered angiogenesis, and excessive extracellular collagen deposition—factors that contribute to the development of pathological scars. Furthermore, PTEN can influence tumor angiogenesis via its interaction with matrix metalloproteinases, which are also expressed in keloid scars.

2. Nuclear factor κB (NF-κB) NF-κB plays a pivotal role in the regulation of cell apoptosis and proliferation. The NF-κB signaling pathway is integral to the entire biological process of wound repair and healing, encompassing inflammatory responses, immune reactions, oxidative stress, and apoptosis, thereby contributing significantly to normal epidermal development and homeostasis. In keloid tissue, this pathway is characterized by persistent inflammation, dysregulated immune function, and infiltrative growth—features that confer tumor-like properties—alongside delayed or insufficient fibroblast apoptosis, aberrant proliferation, angiogenesis, and other pathological phenomena. Moreover, activation of the NF-κB signaling cascade can modulate the activation of proto‑oncogenes such as c‑myc and c‑fos, thereby promoting…

Enhanced Bcl-2 expression and Fas dysfunction lead to impaired fibroblast differentiation and reduced apoptosis, while promoting the production of IL‑1, IL‑6, and cyclin D1, thereby stimulating fibroblast proliferation. Consequently, these findings are of fundamental importance for elucidating the complex pathogenic mechanisms underlying keloids.

3 Outlook

Although keloids are benign neoplasms, they exhibit certain biological characteristics of malignant tumors, such as rapid growth, infiltration into surrounding normal tissues, and a high propensity for recurrence following simple excision. Investigating the mechanisms by which cytokines contribute to keloid formation, as well as the consequences of dysregulated gene expression, can lay the groundwork for future genetic diagnostics and therapeutic strategies.

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