Home LiteratureArticle Details
PMID: 10772656 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Blockade of RAGE suppresses periodontitis-associated bone loss in diabetic mice.

The Journal of clinical investigation ·Vol. 105 ·No. 8 ·2000-04-00 ·Pages 1117-24

Lalla E, Lamster IB, Feit M, Huang L, Spessot A, Qu W, Kislinger T, Lu Y, Stern DM, Schmidt AM

Abstract

Diabetes is associated with increased prevalence, severity, and progression of periodontal disease. To test the hypothesis that activation of RAGE (Receptor for Advanced Glycation End products) contributes to the pathogenesis of diabetes-associated periodontitis, we treated diabetic mice, infected with the human periodontal pathogen Porphyromonas gingivalis, with soluble RAGE (sRAGE). sRAGE is the extracellular domain of the receptor, which binds ligand and blocks interaction with, and activation of, cell-surface RAGE. Blockade of RAGE diminished alveolar bone loss in a dose-dependent manner. Moreover, we noted decreased generation of the proinflammatory cytokines TNF-alpha and IL-6 in gingival tissue, as well as decreased levels of matrix metalloproteinases. Gingival AGEs were also reduced in mice treated with sRAGE, paralleling the observed suppression in alveolar bone loss. These findings link RAGE and exaggerated inflammatory responses to the pathogenesis of destructive periodontal disease in diabetes.

MeSH Terms
Alveolar Bone Loss/etiology,immunology,metabolism,prevention & control Animals Bacteroidaceae Infections/complications,etiology,immunology,metabolism Diabetes Mellitus, Experimental/complications Disease Models, Animal Glycation End Products, Advanced/administration & dosage,metabolism Humans Interleukin-6/metabolism Male Matrix Metalloproteinase 2/metabolism Matrix Metalloproteinase 3/metabolism Matrix Metalloproteinase 9/metabolism Mice Mice, Inbred C57BL Periodontitis/complications,etiology,immunology,metabolism Porphyromonas gingivalis/immunology,pathogenicity Receptor for Advanced Glycation End Products Receptors, Immunologic/antagonists & inhibitors,immunology,physiology Tumor Necrosis Factor-alpha/metabolism
Chemicals
Glycation End Products, Advanced Interleukin-6 Receptor for Advanced Glycation End Products Receptors, Immunologic Tumor Necrosis Factor-alpha Matrix Metalloproteinase 3 Matrix Metalloproteinase 2 Matrix Metalloproteinase 9
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Lalla E
Division of Periodontics, School of Dental and Oral Surgery, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. [email protected]
Lamster I B
Feit M
Huang L
Spessot A
Qu W
Kislinger T
Lu Y
Stern D M
Schmidt A M
References (55)
55 references, click to expand
  1. N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression.
    J Biol Chem. 1999 Oct 29;274(44):31740-9 PMID: 10531386
  2. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides.
    Cell. 1999 Jun 25;97(7):889-901 PMID: 10399917
  3. Comparison of neutrophil chemotactic response in diabetic patients with mild and severe periodontal disease.
    J Periodontol. 1981 Aug;52(8):410-5 PMID: 7021793
  4. Prevalence of periodontal disease in insulin-dependent diabetes mellitus (juvenile diabetes).
    J Am Dent Assoc. 1982 May;104(5):653-60 PMID: 7042797
  5. Diabetes increases collagenase activity in extracts of rat gingiva and skin.
    J Periodontal Res. 1983 Jan;18(1):23-30 PMID: 6304279
  6. Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action.
    J Periodontal Res. 1983 Sep;18(5):516-26 PMID: 6315909
  7. Coronary heart disease in young type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors.
    Diabetologia. 1987 Mar;30(3):144-8 PMID: 3582820
  8. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications.
    N Engl J Med. 1988 May 19;318(20):1315-21 PMID: 3283558
  9. Endotoxin-stimulated human monocyte secretion of interleukin 1, tumour necrosis factor alpha, and prostaglandin E2 shows stable interindividual differences.
    Scand J Immunol. 1988 Jun;27(6):705-16 PMID: 3260683
  10. Altering the progression of human alveolar bone loss with the non-steroidal anti-inflammatory drug flurbiprofen.
    J Periodontol. 1989 Sep;60(9):485-90 PMID: 2677301
  11. 5-year incidence of atherosclerotic vascular disease in relation to general risk factors, insulin level, and abnormalities in lipoprotein composition in non-insulin-dependent diabetic and nondiabetic subjects.
    Circulation. 1990 Jul;82(1):27-36 PMID: 2194696
  12. Type 2 diabetes mellitus and periodontal disease.
    J Am Dent Assoc. 1990 Oct;121(4):532-6 PMID: 2212346
  13. Effects of topical applications of meclofenamic acid and ibuprofen on bone loss, subgingival microbiota and gingival PMN response in the primate Macaca fascicularis.
    J Periodontal Res. 1990 Sep;25(5):300-7 PMID: 2145415
  14. A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women.
    Arch Intern Med. 1991 Jun;151(6):1141-7 PMID: 2043016
  15. Tissue levels of bone resorptive cytokines in periodontal disease.
    J Periodontol. 1991 Aug;62(8):504-9 PMID: 1920018
  16. Host mediators in gingival crevicular fluid: implications for the pathogenesis of periodontal disease.
    Crit Rev Oral Biol Med. 1992;3(1-2):31-60 PMID: 1730070
  17. Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface.
    J Biol Chem. 1992 Jul 25;267(21):14987-97 PMID: 1321822
  18. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins.
    J Biol Chem. 1992 Jul 25;267(21):14998-5004 PMID: 1378843
  19. Glucose and diabetic vascular disease.
    FASEB J. 1992 Aug;6(11):2905-14 PMID: 1644256
  20. Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: a twenty-three year follow-up study.
    Kidney Int. 1992 Apr;41(4):836-9 PMID: 1513106
  21. Periodontopathic potential of two strains of Porphyromonas gingivalis in gnotobiotic rats.
    Arch Oral Biol. 1992 Oct;37(10):813-9 PMID: 1359858
  22. Tetracycline administration increases protein (presumably procollagen) synthesis and secretion in periodontal ligament fibroblasts of streptozotocin-induced diabetic rats.
    J Periodontal Res. 1992 Nov;27(6):631-9 PMID: 1460549
  23. Periodontal disease. The sixth complication of diabetes mellitus.
    Diabetes Care. 1993 Jan;16(1):329-34 PMID: 8422804
  24. Dental disease and risk of coronary heart disease and mortality.
    BMJ. 1993 Mar 13;306(6879):688-91 PMID: 8471920
  25. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues.
    Am J Pathol. 1993 Dec;143(6):1699-712 PMID: 8256857
  26. Tetracyclines inhibit Porphyromonas gingivalis-induced alveolar bone loss in rats by a non-antimicrobial mechanism.
    J Periodontal Res. 1994 Jul;29(4):242-9 PMID: 7932017
  27. Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency.
    Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9441-5 PMID: 7937786
  28. The S100 protein family: history, function, and expression.
    Brain Res Bull. 1995;37(4):417-29 PMID: 7620916
  29. The dark side of glucose.
    Nat Med. 1995 Oct;1(10):1002-4 PMID: 7489352
  30. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats.
    J Clin Invest. 1996 Jan 1;97(1):238-43 PMID: 8550841
  31. The S100 family of EF-hand calcium-binding proteins: functions and pathology.
    Trends Biochem Sci. 1996 Apr;21(4):134-40 PMID: 8701470
  32. Prostaglandin production via induction of cyclooxygenase-2 by human gingival fibroblasts stimulated with lipopolysaccharides.
    Inflammation. 1996 Oct;20(5):555-68 PMID: 8894718
  33. Monocytic TNF alpha secretion patterns in IDDM patients with periodontal diseases.
    J Clin Periodontol. 1997 Jan;24(1):8-16 PMID: 9049792
  34. Inflammatory mediator response as a potential risk marker for periodontal diseases in insulin-dependent diabetes mellitus patients.
    J Periodontol. 1997 Feb;68(2):127-35 PMID: 9058329
  35. Consensus report. Non-surgical pocket therapy: mechanical, pharmacotherapeutics, and dental occlusion.
    Ann Periodontol. 1996 Nov;1(1):581-8 PMID: 9118271
  36. Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products.
    J Biol Chem. 1997 Jun 27;272(26):16498-506 PMID: 9195959
  37. Treatment of periodontal disease in diabetics reduces glycated hemoglobin.
    J Periodontol. 1997 Aug;68(8):713-9 PMID: 9287060
  38. Morphometric analysis of cellular and vascular changes in gingival connective tissue in long-term insulin-dependent diabetes.
    J Periodontol. 1997 Dec;68(12):1237-45 PMID: 9444601
  39. Mechanisms of connective tissue matrix destruction in periodontitis.
    Periodontol 2000. 1997 Jun;14:144-57 PMID: 9567969
  40. Beta 2-microglobulin modified with advanced glycation end products modulates collagen synthesis by human fibroblasts.
    Kidney Int. 1998 May;53(5):1365-73 PMID: 9573554
  41. A chemically modified tetracycline inhibits streptozotocin-induced diabetic depression of skin collagen synthesis and steady-state type I procollagen mRNA.
    Biochim Biophys Acta. 1998 Apr 24;1402(3):250-60 PMID: 9606983
  42. The role of IL-6 type cytokines and their receptors in bone.
    Ann N Y Acad Sci. 1998 May 1;840:194-204 PMID: 9629251
  43. Periodontitis: a risk factor for coronary heart disease?
    Ann Periodontol. 1998 Jul;3(1):127-41 PMID: 9722697
  44. Mode of action of interleukin-6 on mature osteoclasts. Novel interactions with extracellular Ca2+ sensing in the regulation of osteoclastic bone resorption.
    J Cell Biol. 1998 Sep 7;142(5):1347-56 PMID: 9732294
  45. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts.
    Nat Med. 1998 Sep;4(9):1025-31 PMID: 9734395
  46. Is type II diabetes mellitus a disease of the innate immune system?
    Diabetologia. 1998 Oct;41(10):1241-8 PMID: 9794114
  47. A murine model of accelerated periodontal disease in diabetes.
    J Periodontal Res. 1998 Oct;33(7):387-99 PMID: 9842504
  48. Atherosclerosis--an inflammatory disease.
    N Engl J Med. 1999 Jan 14;340(2):115-26 PMID: 9887164
  49. Interleukin-1 and tumor necrosis factor antagonists inhibit the progression of inflammatory cell infiltration toward alveolar bone in experimental periodontitis.
    J Periodontol. 1998 Dec;69(12):1419-25 PMID: 9926773
  50. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms.
    Adv Dent Res. 1998 Nov;12(2):12-26 PMID: 9972117
  51. Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis.
    Circ Res. 1999 Mar 19;84(5):489-97 PMID: 10082470
  52. Oral pathogens: from dental plaque to cardiac disease.
    Curr Opin Microbiol. 1998 Feb;1(1):88-95 PMID: 10066462
  53. Plasma concentration of C-reactive protein is increased in type I diabetic patients without clinical macroangiopathy and correlates with markers of endothelial dysfunction: evidence for chronic inflammation.
    Diabetologia. 1999 Mar;42(3):351-7 PMID: 10096789
  54. Periodontal disease and risk of fatal coronary heart and cerebrovascular diseases.
    J Cardiovasc Risk. 1999 Feb;6(1):7-11 PMID: 10197286
  55. Neutrophil chemotaxis in individuals with advanced periodontal disease and a genetic predisposition to diabetes mellitus.
    J Periodontol. 1981 Apr;52(4):167-73 PMID: 6939837
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI8942
Email
[email protected]
Published
2000-04-00
Pages
1117-24
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC300834
Subset
IM
Grants
NHLBI NIH HHS · P01 HL060901 · United States
NIDCR NIH HHS · DE11561 · United States
NHLBI NIH HHS · HL60901 · United States
External Links
PubMed source DOI: 10.1172/JCI8942 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2