The disparity of this condition between particular subpopulations also seems to have a familial component: both autosomal recessive and autosomal dominant inheritance patterns have been found.¹ Keloids are related to other fibrotic conditions such as systemic sclerosis, eosinophilia-myalgia syndrome, epidemic toxic oil syndrome, eosinophilic fasciitis, localized forms of scleroderma and fibrosing colonopathy.³

Keloids are different from hypertrophic scars in several ways. Both grow outward from the skin, but keloids extend beyond the original boundaries of the wound, while hypertrophic scars do not. Keloids also project high above the plane of the skin, although they usually do not extend deep within the dermis as do hypertrophic scars. Keloids are usually reddish or purplish in color, while hypertrophic scars are white or become white over time.⁴ Also, keloids are much more likely to recur after treatment for removal or reduction; in one study, 60 percent of scars classified as keloids recurred, while only 10 percent of hypertrophic scars recurred.¹

	MOLECULAR DEFECTS CONTRIBUTE TO KELOID SCARRING

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Abnormal molecular defects may contribute to the pathogenesis of fibrotic disorders such as keloid scarring. Keloid research theorizes that the condition may be related to the regulation associated with the wound-healing process. Related etiologic theories include the idea that keloids may result from abnormal signals such as growth factors or cytokines, their cognate cell surface receptors, multiple signal transduction pathways that span from the cell surface to the nucleus, nuclear-level transcription controls or a combination thereof.

Evidence has been found that keloids contain higher numbers of fibroblasts compared with other types of scars. In addition, chemical levels of adenosine triphosphate in keloids are high and remain high months after the injury or laceration. This suggests that cell intermediate metabolism activity is continuing at a high rate.⁵

Additional scientific evidence suggests that there are inherent genetic differences between fibroblasts in keloids contrasted to comparable, but normal, "nonkeloid" epidermal tissues within the same patient.

During keloid formation, plasminogen activator inhibitor type 1, or PAI-1, is elevated, possibly because fibroblasts derived from keloids overexpress PAI-1 messenger RNA, or mRNA, transcripts compared with normal skin fibroblasts.⁶ PAI-1 is a secreted protein also known to be involved in tissue invasion in neoplastic tumor cells. The elevated PAI-1 level may affect protein degradation, as well as subsequent repair steps that, when abnormal, result in keloids and other fibrotic conditions.⁷

Keloids also are linked clinically to the cytokine transforming growth factor ß, or TGF-ß. In vitro tests have shown that TGF-ß is responsible for the activation of fibroblasts and their production, as well as the synthesis, secretion and extracellular matrix deposition and assembly of collagens and proteoglycans. Three isoforms of TGF-ß have been identified in mammals (TGF-ß₁, ß₂ and ß₃). TGF-ß₁ and TGF-ß₂ are now known to promote fibrosis and scar formation, whereas results on TGF-ß₃ are less specific at this time.⁸

TGF-ß₁ and ß₂ proteins are found at higher levels in keloid fibroblast cell cultures compared with normal human dermal fibroblast cultures.⁸ The addition of exogenous TGF-ß₂ to keloid specimens produces a dose-response pattern, inducing high levels of cell proliferation.⁹ Adding TGF-ß₁ causes a sharp increase in collagen synthesis and secretion by keloid fibroblasts, but not by normal fibroblasts.¹⁰

	GROWTH FACTORS AND KELOIDS

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Other growth factors, such as platelet-derived growth factor, or PDGF, and insulinlike growth factor 1, or IGF-1, also are known to regulate cell proliferation, differentiation and growth. TGF-ß seems to "turn on" PDGF receptors and IGF-1 receptors in unusually high numbers in keloid fibroblasts, but not in normal ones.^11,12

Overactivity of PDGF also has been implicated in other fibrotic conditions and in atherosclerosis.¹³ Connective tissue growth factor, or CTGF, also is activated by TGF-ß. High levels of CTGF gene expression have been found in patients with keloids, localized scleroderma and other sclerotic disorders.¹⁴ These types of investigations suggest that the control of synthesis and secretion relative to degradation becomes uncoupled in keloid patients.

Another line of evidence suggests that the aberration in keloid fibroblasts may be the result of a hindered capacity for DNA repair. Researchers irradiated normal and keloid fibroblasts to induce DNA damage and found both types of cells were equally susceptible to the damage. After an incubation period, however, the keloid-derived fibroblasts retained more damage than did the normal cells, indicating that normal repair mechanisms were not operating properly.¹⁵

In addition, scientific research on keloid formation, and in the more general area of wound healing, has discovered several regulatory genes important in the process. A gene called Smad3 produces a protein that mediates TGF-ß levels. Researchers studying knockout mice (mice that lacked the Smad3 gene) found that these mice healed more quickly after injury. The mice had less extracellular matrix protein accumulation and less vascular connective tissue on their wounded surfaces. TGF-ß regulates both of these processes.¹⁶

Laboratory studies have shown that keloid tissue expresses proteins made by the p53 and bcl-2 genes; normal skin generally does not.¹⁷ Both genes are well-known in the oncology field—mutations in p53 have been implicated in up to one-half of all human neoplastic diseases. Researchers also have found p53 mutations in keloid tissue but not in normal tissue. These mutations in genes known to regulate the cell cycle may explain the observed increased cell proliferation and decreased apoptosis resulting in an abnormal molecular process leading to keloid formation.¹⁸

In three-dimensional cell and tissue cultures, keloid fibroblasts also expressed high levels of mRNA for two genes that code for collagens. There may be a defect in these cells that renders them unable to turn off collagen production.¹⁹

	CLINICAL MANAGEMENT OF KELOIDS

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Meanwhile, the clinical management of keloids in dentistry and medicine includes dressings and pressure devices, compression therapy, corticosteroid injections, cryosurgery, excision, radiation therapy, laser therapy, interferon therapy and other therapies directed at collagen synthesis.

Surgery alone results in keloid recurrence in 45 to 100 percent of cases. However, a combination of surgery and corticosteroid therapy also has shown promising results, particularly in recurrent keloid lesions. After removal or reduction of keloid scarring, steroid injections can reduce keloid recurrence to less than 50 percent. Cryosurgery—freezing the growths—is most effective when combined with corticosteroids as well.²⁰

Inhibiting vascular restenosis using radiation is a new frontier in the radiation therapy field, but it appears to be another effective clinical approach for the management of keloids.²¹ This approach also may offer insight into how best to treat benign disorders other than keloids.²¹ Pulsed-dye lasers offer symptomatic improvement for keloid patients, and biotherapy with interferons has been used to decrease scar height and reduce the number of postoperative recurrences.²²

Silicone gel dressings also are used to treat keloids after their removal, although the exact mechanisms of action responsible for their clinical effectiveness are unknown. One theory holds that static electricity generated by friction could be the reason behind their anti-scarring effects. Research comparing a liquid silicone gel cushion with silicone gel sheeting found that both treatments were effective and there was no statistically significant difference between them.²³

Compared with normal cells in culture, fibroblasts from keloids seem to be more sensitive to agents such as pheniramine maleate, an anti-allergic agent, suggesting that pharmacogenetics may be informative. In one study, DNA synthesis and cell proliferation rates in keloid fibroblasts were reduced by more than 60 percent with drug therapy, while normal cell fibroblasts were reduced by only 39 percent.²⁴

Another anti-allergic drug under study for the treatment of keloids is tranilast, which suppresses the release of cytokines such as PDGF, TGF-ß₁ and interleukin-1ß and prevents keloid formation. In patients receiving angioplasty, tranilast treatment lasting three months markedly reduced the restenosis rate.²⁵

New treatments are in the pipeline. These include tamoxifen, a synthetic estrogen used to treat breast cancer. This drug has been shown to inhibit keloid fibroblast proliferation, possibly by decreasing TGF-ß production.²⁶

	CONCLUSION

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As we begin a new decade in a new century, we have many unsolved clinical problems that require extensive research. Ironically, we have much to learn about the etiology, pathogenesis and clinical management of keloids. Research that will almost certainly incorporate molecular epidemiology, genomics and functional genomics, can accelerate an understanding of the molecular mechanisms required for wound healing and the eventual control of the painful and disfiguring consequences of keloids. In tandem, these "next-generation studies" also will further knit together those of us who provide dental and medical health care for all people.