Evaluation of the Role of High-Mobility Group Box 1 Protein in Patients With Keloids

A Case Control Study

Omar Ahmad Azzam, MD; Marwa Salah El-Mesidy, MD; Moataz Maher Kamel, MD; Amira Basyouny Nouh, MBBch


Wounds. 2019;31(7):179-183. 

In This Article

Abstract and Introduction


Background: Keloids cause cosmetic problems, pain, and pruritus. Different modes of therapy are limited by their efficacy and side effects. High-mobility group box 1 protein (HMGB1) may play a role in keloid pathogenesis; therefore, the therapeutic potential of box A1, an antireceptor of advanced glycation end products antibody, and other inhibitors of HMGB1 may play a role in the treatment of keloids.

Objective: This study evaluates the role of HMGB1 in patients with keloids by comparing their serum level with healthy controls.

Materials and Methods: Forty patients with keloids and 40 controls were enrolled in this study. Detailed history and clinical evaluation were performed. A 3-mL sample of whole blood was obtained from both patient groups and centrifuged immediately. The resultant supernatant serum was frozen at -20°C for the detection and quantification of HMGB1 using enzyme-linked immunosorbent assay.

Results: There was a statistically significant elevation in the mean value of HMGB1 in keloid cases (74.38 ± 40.16) compared with the mean value of the controls (52.00 ± 5.41; P = .001). Mean value of HMGB1 was positively correlated with keloid severity.

Conclusions: High-mobility group box 1 was found to be elevated in patients with keloids compared with their controls, suggesting its role in excessive scarring and the role of its antagonists in therapy.


Keloids are abnormalities of wound healing characterized by excessive production of collagen in the skin. In addition to the cosmetic problems caused by a raised and red appearance, keloids can cause pain, pruritus, and contractures. Keloids are visualized as scars that grow beyond the boundaries of the original wound and rarely regress over time. Although seen in patients of all races, keloids have a greater occurrence in dark-skinned individuals, with an incidence of 6% to 16% in African populations.[1]

Large keloids can arise from minor injuries to the skin, such as acne and piercings.[2] Keloids develop from an improper balance between deposition and degradation of extracellular matrix (ECM) components, notably collagen. The excess collagen is produced by malfunctioning fibroblasts due to increased density and activation of growth factor receptors.[3]

High-mobility group box 1 protein (HMGB1) has dual functions. As an intracellular transcription factor, HMGB1 binds to bent DNA to promote the assembly of nucleoprotein complexes, which is critical in the processes of transcription, recombination, replication, and repair. As an extracellular mediator, HMGB1 acts as a potent inflammatory cytokine.[4] Release of HMGB1 occurs actively by stimulated monocytes and macrophages and passively by necrotic/damaged cells.[5] The protein exerts its effects by binding to cell surface receptors, particularly the advanced glycation end product (RAGE) receptor and toll-like receptor (TLR) 2 and TLR4.[6] It affects wound healing by binding primarily to RAGE then translocating to the nucleus where it presumably alters gene expression, resulting in increased viability, proliferation, and migration of keratinocytes and fibroblasts. Several studies[4,7] have elucidated a potential role of HMGB1 in wound healing in murine and human models.

In diabetic murine skin with both reduced HMGB1 levels and altered wound healing, adding HMGB1 increased fibroblast migration and wound closure rates.[7] Although these studies[4,7] support the role of HMGB1 as a promoter of wound closure, the role of HMGB1 in scars remains unclear. By increasing the viability, proliferation, and migration of fibroblasts, HMGB1 presumably could contribute as a profibrotic molecule to produce collagen.

Dardenne et al[8] reported that HMGB1, when applied to early embryonic (before embryonic day 16) murine skin wounds that normally heal with an absence of scar tissue, induced wound healing with scarring and fibrosis. In addition, there was a dose-dependent increase in scar size, fibroblast number, and collagen deposition.[8] This correlated with enhanced and prolonged release of HMGB1 and healed via scar formation in wounds generated beyond murine embryonic day 16.[8] However, Zhang et al[9] concluded that HMGB1 decreases in vitro rat fibroblast collagen synthesis.

The excess production of collagen seen in keloids could result from excess HMGB1 or increased responsiveness of fibroblasts to HMGB1, suggesting similar effects of HMGB1 and transforming growth factor beta (TGF-β) on the induction of keloids. If HMGB1 is elevated in these conditions, the therapeutic potential of mitogen-activated protein kinase kinase inhibitor, box A, glycyrrhizin, the anti-RAGE antibody, and other inhibitors of HMGB1 should be investigated.[4,7]

This case control study evaluates the role of HMGB1 in patients with keloids by comparing the serum level in these patients with healthy controls and correlating the level of HMGB1 with scar severity and duration.