Tauroursodeoxycholic Acid Decreases Keloid Formation by Reducing Endoplasmic Reticulum Stress as Implicated in the Pathogenesis of Keloid.

Sunje Kim,Chungmin Shin,Sangmi Jun,Sang-Ha Oh,Yea Eun Kang,Min-Kyung Yeo,Seong Eun Lee,Harsha Nagar,Cuk-Seong Kim,Yoon-Sun Yi,Shinae Yi

doi:10.3390/ijms221910765

Abstract

Keloids are a common form of pathologic wound healing and are characterized by an excessive production of extracellular matrix. This study examined the major contributing mechanism of human keloid pathogenesis using transcriptomic analysis. We identified the upregulation of mitochondrial oxidative stress response, protein processing in the endoplasmic reticulum, and TGF-β signaling in human keloid tissue samples compared to controls, based on ingenuity pathway and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Electron microscopic examinations revealed an increased number of dysmorphic mitochondria and expanded endoplasmic reticulum (ER) in human keloid tissue samples than that in controls. Western blot analysis performed using human tissues suggested noticeably higher ER stress signaling in keloids than in normal tissues. Treatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, significantly decreased scar formation in rabbit models, compared to normal saline and steroid injections. In summary, our findings demonstrate the contributions of mitochondrial dysfunction and dysregulated ER stress signaling in human keloid formation and the potential of TUDCA in the treatment of keloids.

Highlights

Licensee MDPI, Basel, Switzerland.Keloids are caused by skin injuries such as trauma, piercing, or surgery
The keloid tissues contained damaged mitochondria with low density and broken cristae. These results suggest that dysmorphic mitochondria and endoplasmic reticulum (ER) stress signaling are correlated with keloid pathogenesis
We identified the upregulation of mitochondrial oxidative stress response, protein processing in the endoplasmic reticulum, and TGF-β signaling in human keloids compared to controls, based on ingenuity pathway analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG)

Summary

Introduction

Keloids are caused by skin injuries such as trauma, piercing, or surgery. Due to increased synthesis and reduced degradation of the extracellular matrix (ECM), excessive collagen accumulates in the dermis and the subcutaneous fat layer, resulting in the formation of excessive scar tissue in the injured area. Keloids cause esthetic issues and functional problems such as severe pain, itching, and restriction of movement at the lesion site, which affect the quality of life of the patient [1,2]. Deposition and the mechanism of symptom development remain unclear [3,4]. Genetics, [5] mechanical factors, [6] ischemia, [4] and autoimmunity [7] are implicated in keloid formation. Its pathogenesis remains unclear, thereby inhibiting therapeutic development. Current treatment options, including surgery, [8] silicone sheets, [9]

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Discussion

Conclusion