Caveolin-1 Controls Hyperresponsiveness to Mechanical Stimuli and Fibrogenesis-Associated RUNX2 Activation in Keloid Fibroblasts

Abstract

Keloids are pathological scars characterized by excessive extracellular matrix production that are prone to form in body sites with increased skin tension. CAV1, the principal coat protein of caveolae, has been associated with the regulation of cell mechanics, including cell softening and loss of stiffness sensing ability in NIH3T3 fibroblasts. Although CAV1 is present in low amounts in keloid fibroblasts (KFs), the causal association between CAV1 down-regulation and its aberrant responses to mechanical stimuli remain unclear. In this study, atomic force microscopy showed that KFs were softer than normal fibroblasts with a loss of stiffness sensing. The decrease of CAV1 contributed to the hyperactivation of fibrogenesis-associated RUNX2, a transcription factor germane to osteogenesis/chondrogenesis, and increased migratory ability in KFs. Treatment of KFs with trichostatin A, which increased the acetylation level of histone H3, increased CAV1 and decreased RUNX2 and fibronectin. Trichostatin A treatment also resulted in cell stiffening and decreased migratory ability in KFs. Collectively, these results suggest a role for CAV1 down-regulation in linking the aberrant responsiveness to mechanical stimulation and extracellular matrix accumulation with the progression of keloids, findings that may lead to new developments in the prevention and treatment of keloid scarring.

The tension biology of wound healing

“…On the other hand, this fibrogenetic behaviour of keloid fibroblasts is ameliorated when the cells are seeded on a soft substrate and are accompanied by the downregulation of Runx2 in the nucleus. [87] This study further exemplifies the importance of mechanical force in the pathogenesis of keloids.…”

“…(Permission to reproduce from Akaishi et al [86] ) adhesions and integrin-mediated actin remodelling [90] and has been shown to play an important role in keloids' aberrant responsiveness to mechanical stimulation. [87] Thereafter, peptidergic drugs targeting CAV1 may be a promising strategy. [91] CD47, known as integrin-associated protein (IAP), has shown an anti-fibrotic effect in scleroderma and other fibrosis-related diseases.…”

Systemic factors that shape cutaneous pathological scarring

“…117,118 Second, at the histological level, in neoplasms the parenchymal tumor cells and interstitial fibroblasts are separated; whereas in keloids, they are comprehensively integrated into the quasineoplastic (myo)fibroblasts, with continuous and active cellular proliferation. 3 Third, at the mechanobiological level, KFs are softer than normal fibroblasts and less able to sense changes in ECM stiffness 119 ; such cellular softening is also seen in tumor cells 120 and in fact aids their invasiveness. 121 Fourth, at the metabolic level, KFs, like tumor cells, switch their bioenergetics from mitochondrial oxidative phosphorylation to aerobic glycolysis (as indicated by increased lactate production).…”

Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP

“…To find evidence that this regulation also occurs in vivo, we queried gene expression data obtained by comparing patient-matched normal skin with keloid scars 15 , a fibroproliferative disorder characterized by increased tissue stiffness and whose expansion is linked to mechanical stress 16,17 . Strikingly, several SREBP target genes were consistently and uniformly downregulated in stiffened keloids across all patients, supporting our model ( Fig.…”