Aberrant wound healing: the path to efficacious treatment and prevention of hypertrophic scars and keloids
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Abstract
Hypertrophic scars (HSs) and keloids (KLs) are fibroproliferative scars which arise via aberrations from normal, reparative wound healing of cutaneous tissue following injury to the dermis. Epidemiological data suggest that both scars occur in individuals belonging to a wide range of demographics and are generally common in the global population. Despite this, the current approach to the management of both HSs and KLs – from diagnosis to treatment – is lacking in accuracy and effectiveness. For instance, the highly similar clinical appearance of HSs and KLs complicates differential diagnostics, and our lack of knowledge on the etiology and pathogenesis underlying either scar type has precluded the commercial availability of targeted therapeutic modalities. Consequently, individuals with HSs and KLs may be left to suffer severe and lasting physical and psychological effects that are greatly deleterious to one’s quality of life. Much research is accordingly dedicated to satisfying the pressing need for the optimized management of HSs and KLs. Currently published papers on HSs and KLs have amassed a great number of similarities and differences among these scar types with respect to their clinical appearance, progression, and histopathological findings. Cross-analytical studies of these data have either concluded that HSs and KLs belong to the same disorder, or that they are separate entities. This has ultimately created a divide in the literature regarding the optimal categorization of these scars and their ideal therapeutic procedure(s). However, our currently incomplete understanding of normal wound healing and its pathophysiological deviations is insufficient and cannot yet conclusively prove either theory.
What we do understand of HS and KL pathophysiology, though, is that it involves the sustained, excessive deposition and/or inadequate clearance of ECM as is observed in many other fibrotic diseases. While many factors contribute to this imbalance, a handful of key mediators, such as interleukin-6 (IL-6), transforming growth factor-beta (TGF-β), matrix metalloproteinases (MMPs), and tissue inhibitors of matrix metalloproteinases (TIMPs), are significantly differentially expressed in HSs and KLs and are therefore frequently the focus of developing targeted therapeutics. Unfortunately, the safety and efficacy of many experimental drugs intended to modulate the activity of these aberrantly expressed gene products have yet to be proven in the treatment of these scars. Furthermore, drugs targeting these mediators may not adequately address the multifactorial underpinnings of either scar’s etiology and pathogenesis which may predispose an individual to HSs or KLs.
Epigenetic contribution to aberrant gene expression is therefore emerging as a promising avenue to the optimal management of HSs and KLs. As epigenetic mechanisms are influenced by genetic, systemic, and external factors, further study of DNA methylation patterns, histone modifications, and the regulatory effects of non-coding RNAs could have innumerable benefits. Not only would this deepen our understanding of HS and KL etiology and pathogenesis, but it could also lead us to novel biomarkers that may be pivotal for accurate and efficacious diagnostic, therapeutic, and preventative efforts. With future large-scale comparative studies on the differential gene expression of HS, KL, and control tissues, we may be able to build epigenetic profiles for HSs and KLs. In the event these profiles differ significantly, epigenetic screening of patients may be revolutionary for the differential diagnosis and personalized treatment of HSs and KLs. If not significantly different, these profiles would still be of immense value to our understanding of the pathophysiological mechanisms governing HS and KL formation and lead to the development of more precisely targeted therapies. Either way, the study of epigenetic effects on HS and KL formation can aid in mending the current divide in the literature and lead to the optimal management of HSs and KLs.
Description
2024
License
Attribution-NonCommercial-NoDerivatives 4.0 International