Biomechanical Regulatory Factors and Therapeutic Targets in Keloid Fibrosis

Abstract

Keloids are fibroproliferative skin disorder caused by abnormal healing of injured or irritated skin and are characterized by excessive extracellular matrix (ECM) synthesis and deposition, which results in excessive collagen disorders and calcinosis, increasing the remodeling and stiffness of keloid matrix. The pathogenesis of keloid is very complex, and may include changes in cell function, genetics, inflammation, and other factors. In this review, we aim to discuss the role of biomechanical factors in keloid formation. Mechanical stimulation can lead to excessive proliferation of wound fibroblasts, deposition of ECM, secretion of more pro-fibrosis factors, and continuous increase of keloid matrix stiffness. Matrix mechanics resulting from increased matrix stiffness further activates the fibrotic phenotype of keloid fibroblasts, thus forming a loop that continuously invades the surrounding normal tissue. In this process, mechanical force is one of the initial factors of keloid formation, and matrix mechanics leads to further keloid development. Next, we summarized the mechanotransduction pathways involved in the formation of keloids, such as TGF-β/Smad signaling pathway, integrin signaling pathway, YAP/TAZ signaling pathway, and calcium ion pathway. Finally, some potential biomechanics-based therapeutic concepts and strategies are described in detail. Taken together, these findings underscore the importance of biomechanical factors in the formation and progression of keloids and highlight their regulatory value. These findings may help facilitate the development of pharmacological interventions that can ultimately prevent and reduce keloid formation and progression.

An updated review of the immunological mechanisms of keloid scars

“…Crosstalk between TGF-β and mechanical transduction pathways is increasingly recognized. Among these pathways, the integrin pathway ( 79 , 142 ) and the Hippo/Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) pathway ( 43 , 208 , 209 ) are the most recognized. In addition, TGF-β interacts with Wnt/β-catenin activity in dermal fibroblasts, upregulating ECM genes ( 210 , 211 ).…”

“…The etiology of keloids is likely multifactorial and hinges on a constellation of factors, including genetic predisposition ( 26 – 34 ), inflammation ( 35 – 39 ), mechanical stress ( 40 – 43 ), tissue hypoxia ( 44 – 48 ), delayed-type hypersensitivity ( 49 ), and metabolic dysfunction ( 50 , 51 ). Familial cases of autosomal dominant inheritance with incomplete clinical penetrance and variable expression have been described ( 52 – 54 ).…”

Therapy of pathological scars

“…M2 macrophages‐associated genes are overexpressed in keloids and fibroblasts are increasingly recruited and converted into myofibroblasts by enhanced secretion of growth factors 55 . Local activation of mechanotransduction signaling pathways may also explain the spread of keloidal scar tissue beyond the wound borders 56–58 . The high recurrence rate may be related to the increased presence of memory T cells in keloid tissue 59 …”

The deubiquitinating enzyme USP37 promotes keloid fibroblasts proliferation and collagen production by regulating the c‐Myc expression

“…Keloid is a group of pathological fibroproliferative skin disorders with unremitting extracellular matrix (ECM) accumulation, remodelling, and stiffness 1,2 . Although the pathogenesis of keloid is complex, strong genetic predisposition, growth factors' profile alteration, collagen turnover, and higher stretching tension contribute to keloid formation and development 3‐5 . Surgery, steroid, and radiation treatment are recommended in clinics, while the high recurrence and accompanying psychological distress still pose a challenge for affected patients 6,7 …”

“…1,2 Although the pathogenesis of keloid is complex, strong genetic predisposition, growth factors' profile alteration, collagen turnover, and higher stretching tension contribute to keloid formation and development. [3][4][5] Surgery, steroid, and radiation treatment are recommended in clinics, while the high recurrence and accompanying psychological distress still pose a challenge for affected patients. 6,7 Myofibroblasts derived from resident skin fibroblasts are the principal mediators responsible for ECM accumulation, demonstrating apoptosis resistance and hyperproliferation characteristics.…”