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High-mobility Group Box Protein-1, Matrix Metalloproteinases, and Vitamin D in Keloids and Hypertrophic Scars.

Lee DE, Trowbridge RM, Ayoub NT, Agrawal DK - Plast Reconstr Surg Glob Open (2015)

Bottom Line: This review focuses on the role of high-mobility group box protein-1 (HMGB-1), matrix metalloproteinases (MMPs), and vitamin D in these conditions.MMPs contribute extensively to wound healing and characteristically degrade the extracellular matrix.Additionally, vitamin D may exert an antifibrotic effect partially mediated by MMPs.

View Article: PubMed Central - PubMed

Affiliation: Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Neb.; Brigham and Women's Hospital, Boston, Mass.; and Westfield Plastic Surgery Center, Omaha, Neb.

ABSTRACT
Keloids and hypertrophic scars represent excessive wound healing involving high production of collagen by skin fibroblasts. This review focuses on the role of high-mobility group box protein-1 (HMGB-1), matrix metalloproteinases (MMPs), and vitamin D in these conditions. Although the role of HMGB-1 in keloids and hypertrophic scars is unclear, the effect of HMGB-1 on fibroblasts suggests a profibrotic role and a potential contribution to excessive scarring. MMPs contribute extensively to wound healing and characteristically degrade the extracellular matrix. MMP-1 is decreased in keloids and hypertrophic scars. However, other MMPs, including MMP-2, have been found to be increased and are thought to possibly contribute to keloid expansion through peripheral extracellular matrix catabolism. Many novel therapeutic approaches to keloids and hypertrophic scars target MMPs and aim to increase their levels and catabolic activity. The higher prevalence of keloids in darker skin types may partially be due to a tendency for lower vitamin D levels. The physiologically active form of vitamin D, 1,25(OH)2D3, inhibits the proliferation of keloid fibroblasts, and correlations between vitamin D receptor polymorphisms, such as the TaqI CC genotype, and keloid formation have been reported. Additionally, vitamin D may exert an antifibrotic effect partially mediated by MMPs. Here, we critically discuss whether keloid and hypertrophic scar formation could be predicted based on vitamin D status and vitamin D receptor polymorphisms. Specifically, the findings identified HMGB-1, MMPs, and vitamin D as potential avenues for further clinical investigation and potentially novel therapeutic approaches to prevent the development of keloids and hypertrophic scars.

No MeSH data available.


Related in: MedlinePlus

The role of HMGB-1 in wound healing. HMGB-1 is released actively by stimulated monocytes and macrophages and passively by necrotic/damaged cells.5,6 It exerts its effects by binding to cell surface receptors (on keratinocytes and fibroblasts), particularly the RAGE and the TLRs 2 and 4.7,8 HMGB-1 exerts its effects on wound healing by binding primarily to RAGE and activating MEK1/2, which then activates ERK1/2.9,10 ERK1/2 then translocates to the nucleus, where it presumably alters gene expression, resulting in increased viability, proliferation, and migration of keratinocytes and fibroblasts.9–13 Inhibitors of HMGB-1 activity, along with their specific points of intervention, are also shown.9–11 TLRs indicates toll-like receptors.
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Figure 1: The role of HMGB-1 in wound healing. HMGB-1 is released actively by stimulated monocytes and macrophages and passively by necrotic/damaged cells.5,6 It exerts its effects by binding to cell surface receptors (on keratinocytes and fibroblasts), particularly the RAGE and the TLRs 2 and 4.7,8 HMGB-1 exerts its effects on wound healing by binding primarily to RAGE and activating MEK1/2, which then activates ERK1/2.9,10 ERK1/2 then translocates to the nucleus, where it presumably alters gene expression, resulting in increased viability, proliferation, and migration of keratinocytes and fibroblasts.9–13 Inhibitors of HMGB-1 activity, along with their specific points of intervention, are also shown.9–11 TLRs indicates toll-like receptors.

Mentions: High-mobility group box protein-1 (HMGB-1) has dual functions. As an intracellular transcription factor, HMGB-1 binds to bent DNA to promote the assembly of nucleoprotein complexes, which is critical in the process of transcription, recombination, replication, and repair. As an extracellular mediator, HMGB-1 acts as a potent inflammatory cytokine.4 Release of HMGB-1 occurs actively by stimulated monocytes and macrophages and passively by necrotic/damaged cells (Fig. 1).5,6 HMGB-1 exerts its effects by binding to cell surface receptors, particularly the receptor for advanced glycation end products (RAGE) and the toll-like receptors 2 and 4.7,8


High-mobility Group Box Protein-1, Matrix Metalloproteinases, and Vitamin D in Keloids and Hypertrophic Scars.

Lee DE, Trowbridge RM, Ayoub NT, Agrawal DK - Plast Reconstr Surg Glob Open (2015)

The role of HMGB-1 in wound healing. HMGB-1 is released actively by stimulated monocytes and macrophages and passively by necrotic/damaged cells.5,6 It exerts its effects by binding to cell surface receptors (on keratinocytes and fibroblasts), particularly the RAGE and the TLRs 2 and 4.7,8 HMGB-1 exerts its effects on wound healing by binding primarily to RAGE and activating MEK1/2, which then activates ERK1/2.9,10 ERK1/2 then translocates to the nucleus, where it presumably alters gene expression, resulting in increased viability, proliferation, and migration of keratinocytes and fibroblasts.9–13 Inhibitors of HMGB-1 activity, along with their specific points of intervention, are also shown.9–11 TLRs indicates toll-like receptors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4494495&req=5

Figure 1: The role of HMGB-1 in wound healing. HMGB-1 is released actively by stimulated monocytes and macrophages and passively by necrotic/damaged cells.5,6 It exerts its effects by binding to cell surface receptors (on keratinocytes and fibroblasts), particularly the RAGE and the TLRs 2 and 4.7,8 HMGB-1 exerts its effects on wound healing by binding primarily to RAGE and activating MEK1/2, which then activates ERK1/2.9,10 ERK1/2 then translocates to the nucleus, where it presumably alters gene expression, resulting in increased viability, proliferation, and migration of keratinocytes and fibroblasts.9–13 Inhibitors of HMGB-1 activity, along with their specific points of intervention, are also shown.9–11 TLRs indicates toll-like receptors.
Mentions: High-mobility group box protein-1 (HMGB-1) has dual functions. As an intracellular transcription factor, HMGB-1 binds to bent DNA to promote the assembly of nucleoprotein complexes, which is critical in the process of transcription, recombination, replication, and repair. As an extracellular mediator, HMGB-1 acts as a potent inflammatory cytokine.4 Release of HMGB-1 occurs actively by stimulated monocytes and macrophages and passively by necrotic/damaged cells (Fig. 1).5,6 HMGB-1 exerts its effects by binding to cell surface receptors, particularly the receptor for advanced glycation end products (RAGE) and the toll-like receptors 2 and 4.7,8

Bottom Line: This review focuses on the role of high-mobility group box protein-1 (HMGB-1), matrix metalloproteinases (MMPs), and vitamin D in these conditions.MMPs contribute extensively to wound healing and characteristically degrade the extracellular matrix.Additionally, vitamin D may exert an antifibrotic effect partially mediated by MMPs.

View Article: PubMed Central - PubMed

Affiliation: Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Neb.; Brigham and Women's Hospital, Boston, Mass.; and Westfield Plastic Surgery Center, Omaha, Neb.

ABSTRACT
Keloids and hypertrophic scars represent excessive wound healing involving high production of collagen by skin fibroblasts. This review focuses on the role of high-mobility group box protein-1 (HMGB-1), matrix metalloproteinases (MMPs), and vitamin D in these conditions. Although the role of HMGB-1 in keloids and hypertrophic scars is unclear, the effect of HMGB-1 on fibroblasts suggests a profibrotic role and a potential contribution to excessive scarring. MMPs contribute extensively to wound healing and characteristically degrade the extracellular matrix. MMP-1 is decreased in keloids and hypertrophic scars. However, other MMPs, including MMP-2, have been found to be increased and are thought to possibly contribute to keloid expansion through peripheral extracellular matrix catabolism. Many novel therapeutic approaches to keloids and hypertrophic scars target MMPs and aim to increase their levels and catabolic activity. The higher prevalence of keloids in darker skin types may partially be due to a tendency for lower vitamin D levels. The physiologically active form of vitamin D, 1,25(OH)2D3, inhibits the proliferation of keloid fibroblasts, and correlations between vitamin D receptor polymorphisms, such as the TaqI CC genotype, and keloid formation have been reported. Additionally, vitamin D may exert an antifibrotic effect partially mediated by MMPs. Here, we critically discuss whether keloid and hypertrophic scar formation could be predicted based on vitamin D status and vitamin D receptor polymorphisms. Specifically, the findings identified HMGB-1, MMPs, and vitamin D as potential avenues for further clinical investigation and potentially novel therapeutic approaches to prevent the development of keloids and hypertrophic scars.

No MeSH data available.


Related in: MedlinePlus