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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

Vitamin D insufficiency may increase one’s propensity for excessive fibrosis. This is due to the ability of 1,25(OH)2D3 to exert a possible antifibrotic effect partially mediated by MMPs. TGF-β was found to decrease MMP-1 production in human keloids,25 and 1,25(OH)2D was found to inhibit TGF-β-induced ECM production.65 1,25(OH)2D3 was also shown to induce expression of HGF,65 an antifibrotic cytokine that increases expression of MMP-1, MMP-2, and MMP-3 in human keloid fibroblasts/keloid tissue (MMP-2 and MMP-3 not shown).28 Finally, 1,25(OH)2D3 increased MMP-9 activity.65 MMP-9 levels were high in the postinjured skin tissue of athymic nude mice, whose skin heals without scar formation.44 Vitamin D insufficiency (indicated by low 25(OH)D levels) would result in low 1,25(OH)2D3, which would increase TGF-β, decrease HGF, and decrease MMP-9 activity. Increased TGF-β and decreased HGF would result in decreased MMP-1, which, along with decreased MMP-9 activity, would result in increased fibrosis. HGF indicates hepatocyte growth factor.
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Figure 2: Vitamin D insufficiency may increase one’s propensity for excessive fibrosis. This is due to the ability of 1,25(OH)2D3 to exert a possible antifibrotic effect partially mediated by MMPs. TGF-β was found to decrease MMP-1 production in human keloids,25 and 1,25(OH)2D was found to inhibit TGF-β-induced ECM production.65 1,25(OH)2D3 was also shown to induce expression of HGF,65 an antifibrotic cytokine that increases expression of MMP-1, MMP-2, and MMP-3 in human keloid fibroblasts/keloid tissue (MMP-2 and MMP-3 not shown).28 Finally, 1,25(OH)2D3 increased MMP-9 activity.65 MMP-9 levels were high in the postinjured skin tissue of athymic nude mice, whose skin heals without scar formation.44 Vitamin D insufficiency (indicated by low 25(OH)D levels) would result in low 1,25(OH)2D3, which would increase TGF-β, decrease HGF, and decrease MMP-9 activity. Increased TGF-β and decreased HGF would result in decreased MMP-1, which, along with decreased MMP-9 activity, would result in increased fibrosis. HGF indicates hepatocyte growth factor.

Mentions: The direct role of HMGB-1, MMPs, and vitamin D in keloids and hypertrophic scars has yet to be elucidated, and a relationship between these 3 factors in the pathogenesis of these conditions henceforth remains unclear. However, findings from current literature suggest a possible interaction between MMPs and vitamin D that could influence scar formation. The aforementioned study by Zhang et al65 found that 1,25(OH)2D3 inhibited TGF-β-induced ECM production, increased MMP-9 activity, and increased expression of hepatocyte growth factor. 1,25(OH)2D3 may, therefore, exert an antifibrotic effect through a mechanism partially mediated by MMPs. Vitamin D insufficiency would then increase the propensity for excessive fibrosis (Fig. 2). The involvement of HMGB-1 is more obscure. A study by Kao et al70 found that HMGB-1 drove in vitro hepatic stellate cells toward fibrogenesis and suppressed the activity of MMP-2 (but not MMP-9). These results coincide with the earlier discussion of HMGB-1 as a profibrotic mediator, but they somewhat conflict with the results of a study by Limana et al,71 who found that HMGB-1, when injected into the failing, infarcted hearts of mice, reduced collagen deposition, increased MMP-2 and MMP-9 activity, and decreased TIMP-3 levels. It is possible that HMGB-1 has different effects on fibrosis and that these effects are location- and/or organ-dependent. Additional studies investigating the role of HMGB-1 in skin fibrosis and MMP activity are needed.


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)

Vitamin D insufficiency may increase one’s propensity for excessive fibrosis. This is due to the ability of 1,25(OH)2D3 to exert a possible antifibrotic effect partially mediated by MMPs. TGF-β was found to decrease MMP-1 production in human keloids,25 and 1,25(OH)2D was found to inhibit TGF-β-induced ECM production.65 1,25(OH)2D3 was also shown to induce expression of HGF,65 an antifibrotic cytokine that increases expression of MMP-1, MMP-2, and MMP-3 in human keloid fibroblasts/keloid tissue (MMP-2 and MMP-3 not shown).28 Finally, 1,25(OH)2D3 increased MMP-9 activity.65 MMP-9 levels were high in the postinjured skin tissue of athymic nude mice, whose skin heals without scar formation.44 Vitamin D insufficiency (indicated by low 25(OH)D levels) would result in low 1,25(OH)2D3, which would increase TGF-β, decrease HGF, and decrease MMP-9 activity. Increased TGF-β and decreased HGF would result in decreased MMP-1, which, along with decreased MMP-9 activity, would result in increased fibrosis. HGF indicates hepatocyte growth factor.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
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Figure 2: Vitamin D insufficiency may increase one’s propensity for excessive fibrosis. This is due to the ability of 1,25(OH)2D3 to exert a possible antifibrotic effect partially mediated by MMPs. TGF-β was found to decrease MMP-1 production in human keloids,25 and 1,25(OH)2D was found to inhibit TGF-β-induced ECM production.65 1,25(OH)2D3 was also shown to induce expression of HGF,65 an antifibrotic cytokine that increases expression of MMP-1, MMP-2, and MMP-3 in human keloid fibroblasts/keloid tissue (MMP-2 and MMP-3 not shown).28 Finally, 1,25(OH)2D3 increased MMP-9 activity.65 MMP-9 levels were high in the postinjured skin tissue of athymic nude mice, whose skin heals without scar formation.44 Vitamin D insufficiency (indicated by low 25(OH)D levels) would result in low 1,25(OH)2D3, which would increase TGF-β, decrease HGF, and decrease MMP-9 activity. Increased TGF-β and decreased HGF would result in decreased MMP-1, which, along with decreased MMP-9 activity, would result in increased fibrosis. HGF indicates hepatocyte growth factor.
Mentions: The direct role of HMGB-1, MMPs, and vitamin D in keloids and hypertrophic scars has yet to be elucidated, and a relationship between these 3 factors in the pathogenesis of these conditions henceforth remains unclear. However, findings from current literature suggest a possible interaction between MMPs and vitamin D that could influence scar formation. The aforementioned study by Zhang et al65 found that 1,25(OH)2D3 inhibited TGF-β-induced ECM production, increased MMP-9 activity, and increased expression of hepatocyte growth factor. 1,25(OH)2D3 may, therefore, exert an antifibrotic effect through a mechanism partially mediated by MMPs. Vitamin D insufficiency would then increase the propensity for excessive fibrosis (Fig. 2). The involvement of HMGB-1 is more obscure. A study by Kao et al70 found that HMGB-1 drove in vitro hepatic stellate cells toward fibrogenesis and suppressed the activity of MMP-2 (but not MMP-9). These results coincide with the earlier discussion of HMGB-1 as a profibrotic mediator, but they somewhat conflict with the results of a study by Limana et al,71 who found that HMGB-1, when injected into the failing, infarcted hearts of mice, reduced collagen deposition, increased MMP-2 and MMP-9 activity, and decreased TIMP-3 levels. It is possible that HMGB-1 has different effects on fibrosis and that these effects are location- and/or organ-dependent. Additional studies investigating the role of HMGB-1 in skin fibrosis and MMP activity are needed.

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