Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer
Introduction Patients with diabetes have increased risk of periodontal disease, with increased risk of weakening of periodontal ligament and tooth loss. Periodontal ligament is produced and maintained by periodontal ligament fibroblasts (PDLFs). We hypothesized that metabolic dysfunction of PDLFs in...
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doaj-fb1bd7acd586448f87d99deb1c96cde52021-01-22T02:30:14ZengBMJ Publishing GroupBMJ Open Diabetes Research & Care2052-48972020-12-018210.1136/bmjdrc-2020-001458Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducerAmal Ashour0Mingzhan Xue1Maryam Al-Motawa2Paul J Thornalley3Naila Rabbani4Speciality Clinics, University Dental Hospital, Taif Dental College, Taif University, Taif, Saudi ArabiaDiabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, QatarDiabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, QatarClinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry, UKDepartment of Basic Medical Science, College of Medicine, QU Health, Qatar University, Doha, QatarIntroduction Patients with diabetes have increased risk of periodontal disease, with increased risk of weakening of periodontal ligament and tooth loss. Periodontal ligament is produced and maintained by periodontal ligament fibroblasts (PDLFs). We hypothesized that metabolic dysfunction of PDLFs in hyperglycemia produces an accumulation of the reactive glycating agent, methylglyoxal (MG), leading to increased formation of the major advanced glycation endproduct, MG-H1 and PDLF dysfunction. The aim of this study was to assess if there is dicarbonyl stress and functional impairment of human PDLFs in primary culture in high glucose concentration—a model of hyperglycemia, to characterize the metabolic drivers of it and explore remedial intervention by the glyoxalase 1 inducer dietary supplement, trans-resveratrol and hesperetin combination (tRES-HESP).Research design and methods Human PDLFs were incubated in low and high glucose concentration in vitro. Metabolic and enzymatic markers of MG and glucose control were quantified and related changes in the cytoplasmic proteome and cell function—binding to collagen-I, assessed. Reversal of PDLF dysfunction by tRES-HESP was explored.Results In high glucose concentration cultures, there was a ca. twofold increase in cellular MG, cellular protein MG-H1 content and decreased attachment of PDLFs to collagen-I. This was driven by increased hexokinase-2 linked glucose metabolism and related increased MG formation. Proteomics analysis revealed increased abundance of chaperonins, heat shock proteins (HSPs), Golgi-to-endoplasmic reticulum transport and ubiquitin E3 ligases involved in misfolded protein degradation in high glucose concentration, consistent with activation of the unfolded protein response by increased misfolded MG-modified proteins. PDLF dysfunction was corrected by tRES-HESP.Conclusions Increased hexokinase-2 linked glucose metabolism produces dicarbonyl stress, increased MG-modified protein, activation of the unfolded protein response and functional impairment of PDLFs in high glucose concentration. tRES-HESP resolves this at source by correcting increased glucose metabolism and may be of benefit in prevention of diabetic periodontal disease.https://drc.bmj.com/content/8/2/e001458.full |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Amal Ashour Mingzhan Xue Maryam Al-Motawa Paul J Thornalley Naila Rabbani |
spellingShingle |
Amal Ashour Mingzhan Xue Maryam Al-Motawa Paul J Thornalley Naila Rabbani Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer BMJ Open Diabetes Research & Care |
author_facet |
Amal Ashour Mingzhan Xue Maryam Al-Motawa Paul J Thornalley Naila Rabbani |
author_sort |
Amal Ashour |
title |
Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer |
title_short |
Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer |
title_full |
Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer |
title_fullStr |
Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer |
title_full_unstemmed |
Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer |
title_sort |
glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer |
publisher |
BMJ Publishing Group |
series |
BMJ Open Diabetes Research & Care |
issn |
2052-4897 |
publishDate |
2020-12-01 |
description |
Introduction Patients with diabetes have increased risk of periodontal disease, with increased risk of weakening of periodontal ligament and tooth loss. Periodontal ligament is produced and maintained by periodontal ligament fibroblasts (PDLFs). We hypothesized that metabolic dysfunction of PDLFs in hyperglycemia produces an accumulation of the reactive glycating agent, methylglyoxal (MG), leading to increased formation of the major advanced glycation endproduct, MG-H1 and PDLF dysfunction. The aim of this study was to assess if there is dicarbonyl stress and functional impairment of human PDLFs in primary culture in high glucose concentration—a model of hyperglycemia, to characterize the metabolic drivers of it and explore remedial intervention by the glyoxalase 1 inducer dietary supplement, trans-resveratrol and hesperetin combination (tRES-HESP).Research design and methods Human PDLFs were incubated in low and high glucose concentration in vitro. Metabolic and enzymatic markers of MG and glucose control were quantified and related changes in the cytoplasmic proteome and cell function—binding to collagen-I, assessed. Reversal of PDLF dysfunction by tRES-HESP was explored.Results In high glucose concentration cultures, there was a ca. twofold increase in cellular MG, cellular protein MG-H1 content and decreased attachment of PDLFs to collagen-I. This was driven by increased hexokinase-2 linked glucose metabolism and related increased MG formation. Proteomics analysis revealed increased abundance of chaperonins, heat shock proteins (HSPs), Golgi-to-endoplasmic reticulum transport and ubiquitin E3 ligases involved in misfolded protein degradation in high glucose concentration, consistent with activation of the unfolded protein response by increased misfolded MG-modified proteins. PDLF dysfunction was corrected by tRES-HESP.Conclusions Increased hexokinase-2 linked glucose metabolism produces dicarbonyl stress, increased MG-modified protein, activation of the unfolded protein response and functional impairment of PDLFs in high glucose concentration. tRES-HESP resolves this at source by correcting increased glucose metabolism and may be of benefit in prevention of diabetic periodontal disease. |
url |
https://drc.bmj.com/content/8/2/e001458.full |
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