Chondroitin Sulfate Promotes the Proliferation of Keloid Fibroblasts Through Activation of the Integrin and Protein Kinase B Pathways.

Yasuhiro Katayama,Naoki Morimoto,Satoko Yamawaki,Toshihiro Ishiko,Hiroshi Kubota,Motoko Naitoh,Rino Aya

doi:10.3390/ijms21061955

Abstract

Keloids are dermal fibroproliferative tumors that arise beyond the boundary of the original wound edges and invades adjacent tissue. Keloids are characterized by the extensive production of extracellular matrix (ECM) and abnormal fibroblast proliferation. Chondroitin sulfate (CS) is one of the major structural components of cartilage and ECM. Recently, we reported the over-accumulation of CS in keloid lesions. Keloid-derived fibroblasts (KFs) and normal dermal fibroblasts (NFs) were incubated with CS. The fibroblast proliferation rate was analyzed using a tetrazolium salt colorimetric assay. The activation of the intracellular signaling pathway was analyzed by Western blotting. Wortmannin, a PI3K inhibitor, and anti-integrin antibodies were tested to investigate the mechanism of the CS-induced cell proliferation. CS strongly stimulated the proliferation of KFs, but not NFs. The analysis of the intracellular signal transduction pathway revealed that the stimulation effect of CS on KF proliferation was due to the activation of the protein kinase B (AKT) pathway and that integrin α1 was responsible for this phenomenon. We revealed that CS probably activates the AKT pathway through integrin to induce KF proliferation. CS may be a novel clinical therapeutic target in keloids.

Highlights

Keloids are benign dermal fibroproliferative tumors that grow beyond the boundary of the original wound edge and invade the adjacent tissue due to the extensive production of extracellular matrix and the abnormal proliferation of fibroblasts [1]
We explored the novel roles of Chondroitin sulfate (CS) in the positive regulation of Keloid-derived fibroblasts (KFs) proliferation by focusing on the promotion of the CS-mediated signaling pathway
We demonstrated that CS played a role in the proliferation of KFs, we could not rule out the possibility that another pathway produces intracellular proliferative signals, like contactin-1 in neural cells [47]

Summary

Introduction

Keloids are benign dermal fibroproliferative tumors that grow beyond the boundary of the original wound edge and invade the adjacent tissue due to the extensive production of extracellular matrix and the abnormal proliferation of fibroblasts [1]. Keloids arise spontaneously or during the wound healing process of the dermis, and rarely regress without treatment. The treatment of keloids has long been a major problem for plastic surgeons due to the high rate of recurrence. Multimodal treatments, including surgical excision, radiotherapy, corticosteroid injection, physical therapy, and combinations of these treatments, have been applied. The mechanism underlying keloid formation remains unclear. Revealing the etiology of keloids is a fundamental step in the development of clinical treatments for the condition

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