Two dicarbonyl compounds, 3-deoxyglucosone and methylglyoxal, differentially modulate dermal fibroblasts

Sassi-Gaha, Sihem; Loughlin, Danielle T.; Kappler, Francis; Schwartz, Michael L.; Su, Bangying; Tobia, Annette M.; Artlett, Carol M.

doi:10.1016/j.matbio.2009.09.007

Cited by 30 publications

(23 citation statements)

References 38 publications

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“…We previously demonstrated that 3DG-collagen inhibits the expression of type I collagen in fibroblasts [10]; therefore, we investigated the role of p38 MAPK in type I collagen production. Fibroblasts were pretreated for 1 h with the inhibitors SB202190, LY294002, PD98059, or a combination of inhibitors were cultured on native collagen or 3DG-collagen for 24 h. Fibroblasts cultured on native collagen induced the expression of collagen at both the level of transcription and translation.…”

Section: Resultsmentioning

confidence: 99%

“…One possible reason for the defective wound healing capacity observed in diabetes could be the presence of the advanced glycation end product precursor 3-deoxyglucosone (3DG). We previously demonstrated that 3DG-modified collagen reduced fibroblast migration [9], proliferation, and ECM production [10] while increasing apoptosis through the activation of p38 mitogen activated protein kinase (MAPK) [11].…”

Section: Introductionmentioning

confidence: 99%

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Modification of Collagen by 3-Deoxyglucosone Alters Wound Healing through Differential Regulation of p38 MAP Kinase

Loughlin

Artlett

2011

PLoS ONE

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BackgroundWound healing is a highly dynamic process that requires signaling from the extracellular matrix to the fibroblasts for migration and proliferation, and closure of the wound. This rate of wound closure is impaired in diabetes, which may be due to the increased levels of the precursor for advanced glycation end products, 3-deoxyglucosone (3DG). Previous studies suggest a differential role for p38 mitogen-activated kinase (MAPK) during wound healing; whereby, p38 MAPK acts as a growth kinase during normal wound healing, but acts as a stress kinase during diabetic wound repair. Therefore, we investigated the signaling cross-talk by which p38 MAPK mediates wound healing in fibroblasts cultured on native collagen and 3DG-collagen.Methodology/Principal FindingsUsing human dermal fibroblasts cultured on 3DG-collagen as a model of diabetic wounds, we demonstrated that p38 MAPK can promote either cell growth or cell death, and this was dependent on the activation of AKT and ERK1/2. Wound closure on native collagen was dependent on p38 MAPK phosphorylation of AKT and ERK1/2. Furthermore, proliferation and collagen production in fibroblasts cultured on native collagen was dependent on p38 MAPK regulation of AKT and ERK1/2. In contrast, 3DG-collagen decreased fibroblast migration, proliferation, and collagen expression through ERK1/2 and AKT downregulation via p38 MAPK.Conclusions/SignificanceTaken together, the present study shows that p38 MAPK is a key signaling molecule that plays a significantly opposite role during times of cellular growth and cellular stress, which may account for the differing rates of wound closure seen in diabetic populations.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modification of Collagen by 3-Deoxyglucosone Alters Wound Healing through Differential Regulation of p38 MAP Kinase

Loughlin

Artlett

2011

PLoS ONE

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“…In addition to the use of AG we studied a new promising therapeutic, meglumine, which decreased caspase-3 activation in the cell by abolishing the production of ROS and activation of GADD153. Additionally, meglumine was shown to reverse the 3DG-collagen mediated effects on fibroblasts by promoting fibroblast migration and proliferation, and increasing ECM production [28], [29]. With the growing number of elderly and diabetic patients, the number of people suffering from diabetic complications associated with AGE formation will continue to increase; therefore, it is vital to gain a better understanding of not only 3DG signaling but of all AGE signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated that 3DG-collagen signals to the fibroblast in an anti-fibrotic way, causing decreased fibroblast migration, proliferation, and extracellular matrix (ECM) production [27]–[29]. In contrast, methylglyoxal (MG), a well studied AGE precursor, has been implicated in pro-fibrotic conditions such as atherosclerosis, and modification of collagen by MG has been shown to increase fibroblast proliferation and ECM production [10], [29]–[31]. Because the varying pathology of the AGEs in diabetes could rely on the dicarbonyl that produces them, it is important to understand the role of apoptosis in the context of independent AGE precursors.…”

Section: Introductionmentioning

confidence: 99%

Precursor of Advanced Glycation End Products Mediates ER-Stress-Induced Caspase-3 Activation of Human Dermal Fibroblasts through NAD(P)H Oxidase 4

Loughlin

Artlett

2010

PLoS ONE

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BackgroundThe precursor for advanced glycation end products, 3-deoxyglucosone (3DG) is highly upregulated in skin explants of diabetic cutaneous wounds, and has been shown to negatively impact dermal fibroblasts, which are crucial in wound remodeling. 3DG induces apoptosis however; the mechanisms involved in the apoptotic action of 3DG in the pathogenesis of diabetic chronic wounds are poorly understood. Therefore, we sought to delineate novel mechanisms involved with the 3DG-collagen induced apoptosis.Methodology/Principal FindingsUsing human dermal fibroblasts, we demonstrated that 3DG-modified collagen induces oxidative stress and caspase-3 activation. Oxidative stress was found to be dependent on the upregulation of NAD(P)H oxidase 4 (Nox4), a reactive oxygen species (ROS) Nox homologue, triggering endoplasmic reticulum (ER) stress, as assessed by the ER stress-induced apoptosis marker Growth Arrest and DNA Damage-inducible gene 153 (GADD153). We demonstrated that 3DG-collagen activated GADD153 via phosphorylation of p38 mitogen activated protein kinase (MAPK), and this was dependent on upstream ROS. Inhibition of ROS and/or p38 MAPK abrogated 3DG-collagen induced caspase-3 activation. Our investigations also demonstrated that 3DG-collagen-induced caspase-3 activation did not signal through the canonical receptor for advanced glycation end products (RAGE) but through integrin α1β1. To further verify the role of integrins, neutralization of integrins α1β1 prevented 3DG-collagen-induced upregulation of ROS, GADD153, and caspase-3 activation; suggesting that 3DG-collagen signaling to the fibroblast is dependent on integrins α1β1.Conclusions/SignificanceTaken together, these findings demonstrate for the first time that a RAGE independent mechanism is involved in 3DG-collagen-induced apoptosis. Moreover, the ER stress pathway through activation of Nox4 by integrins α1β1 plays a key role in 3DG-collagen-induced caspase-3 activation, which may play an important role in the pathogenesis of diabetic wounds.

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“…Highly reactive dicarbonyls attack the lysine, arginine (Arg) and cysteine residues of long-lived proteins, such as collagens, to form irreversible AGEs causing changes in collagen pathophysiology that result in disruption of normal collagen matrix remodeling [45]. …”

Section: Biological Properties Of Mg and Agesmentioning

confidence: 99%

Methylglyoxal—A Potential Risk Factor of Manuka Honey in Healing of Diabetic Ulcers

Majtán

2010

Evidence-Based Complementary and Alternative Medicine

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Honey has been considered as a remedy in wound healing since ancient times. However, as yet, there are inadequate supportive robust randomized trials and experimental data to fully accept honey as an effective medical product in wound care. Manuka honey has been claimed to have therapeutic advantages over other honeys. Recently, it has been documented that the pronounced antibacterial activity of manuka honey is due, at least in part, to reactive methylglyoxal (MG). The concentration of MG in manuka honeys is up to 100-fold higher than in conventional honeys. MG is a potent protein-glycating agent and an important precursor of advanced glycation end products (AGEs). MG and AGEs play a role in the pathogenesis of impaired diabetic wound healing and can modify the structure and function of target molecules. This commentary describes the concern that MG in manuka honey may delay wound healing in diabetic patients. Further detailed research is needed to fully elucidate the participation of honey/derived MG in healing diabetic ulcers. We advocate randomized controlled trials to determine efficacy and safety of manuka honey in this population.

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Two dicarbonyl compounds, 3-deoxyglucosone and methylglyoxal, differentially modulate dermal fibroblasts

Cited by 30 publications

References 38 publications

Modification of Collagen by 3-Deoxyglucosone Alters Wound Healing through Differential Regulation of p38 MAP Kinase

Modification of Collagen by 3-Deoxyglucosone Alters Wound Healing through Differential Regulation of p38 MAP Kinase

Precursor of Advanced Glycation End Products Mediates ER-Stress-Induced Caspase-3 Activation of Human Dermal Fibroblasts through NAD(P)H Oxidase 4

Methylglyoxal—A Potential Risk Factor of Manuka Honey in Healing of Diabetic Ulcers

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