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

Lalla, Evanthia; Lamster, Ira B.; Feit, Michael; Huang, Linda; Spessot, Alexandra; Qu, Wu; Kislinger, Thomas; Lu, Yan; Stern, David M.; Schmidt, Ann Marie

doi:10.1172/jci8942

Cited by 336 publications

(325 citation statements)

References 54 publications

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“…Numerous studies have localized AGEs to the retinal microvessels and basement membrane in both humans and rats (46). These factors can also affect MMP expression and activity (17,47,48). In this study, we examined the role of AGE in MMP upregulation by vascular endothelial cells and in alteration of VE-cadherin expression.…”

Section: Fig 2 Disruption Of Ve-cadherin Causesmentioning

confidence: 98%

Proteolytic Degradation of VE-Cadherin Alters the Blood-Retinal Barrier in Diabetes

et al. 2007

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OBJECTIVE-Increased vascular permeability due to alteration of the blood-retinal barrier (BRB) is one of the major complications in early diabetes. The aim of the present study was to determine whether diabetes alters the cellular expression and distribution of the adherens junction protein vascular endothelial (VE)-cadherin in retinal endothelial cells and if this alteration is mediated by proteinase activity.RESEARCH DESIGN AND METHODS-Diabetes was induced in Brown Norway rats using streptozotocin, and retinal vascular permeability was measured by the Evans blue technique. The expression of matrix metalloproteinases (MMPs) and VE-cadherin was examined in isolated retinal vessels or cultured endothelial cells in response to diabetes and advanced glycation end products (AGEs). The cleavage of VE-cadherin from the endothelial cell surface was monitored by Western blotting following MMP or AGE treatment.RESULTS-Retinal vascular permeability was significantly increased in rats following 2 weeks of diabetes coincident with a decrease of VE-cadherin expression. This increased vascular permeability could be inhibited with an MMP inhibitor. Treatment of endothelial cells with AGE-BSA led to a reduction of VE-cadherin staining on the cell surface and increased permeability, which was MMP mediated. Treatment of cells with specific MMPs or AGEs resulted in cleavage of VE-cadherin from the cell surface. T he normal permeability of the retinal microvasculature is tightly controlled by a series of complex interactions between adjacent endothelial cells and by additional interactions between the endothelial cells and other cell types in the retina, including vascular pericytes, astrocytes, and Mü ller glial cells (1). These interactions form the structural basis of the inner blood-retinal barrier (BRB), which facilitates normal functioning of the neural retina. Disruption of these interactions is anticipated to lead to a compromise of the barrier function, resulting in leakage of plasma constituents into the surrounding retinal tissues and retinal edema. The alteration of the BRB followed by retinal edema are key early events in the pathogenesis of diabetic retinopathy, and macular edema is the leading cause of vision loss in diabetic patients. CONCLUSIONS-TheseEndothelial cells of the retinal microvasculature contribute to the function of the BRB through the formation of specialized intercellular junctions including adherens and tight junctions. The cadherin family of proteins, of which there are more than 80 members, is a primary component of the adherens junctions (2). The vascular endothelial (VE)-cadherin mediates calcium-dependent homophilic adhesion between endothelial cells. In addition, VE-cadherin functions as a plasma membrane attachment site for the cytoskeleton through its interactions with the cytoplasmic proteins ␤-and ␥-catenin (3-5). In addition to contributing to the mechanical attachment of cells, VEcadherin also plays a role in the regulation of a variety of endothelial cell behaviors including motility, m...

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Section: Fig 2 Disruption Of Ve-cadherin Causesmentioning

confidence: 98%

Proteolytic Degradation of VE-Cadherin Alters the Blood-Retinal Barrier in Diabetes

et al. 2007

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“…In this context, recently identified polymorphisms within the promoter of the gene encoding RAGE may hold the key to unique elements controlling enhanced transcription of the RAGE gene and increased expression of cell surface RAGE. 54 As a number of studies have suggested that expression of RAGE is increased at sites of ligand accumulation such as diabetic atherosclerotic lesions, infected periodontium or Alzheimer disease brain, 13,18,55 polymorphisms within regulation elements and/or ligand-binding regions may, alone or in combination, orchestrate RAGE's availability and/or functional potential in a given milieu. 56 In conclusion, we propose that these observations in an animal model of inflammatory arthritis and in S100/calgranulin-stimulated activation of 82S RAGEbearing cells highlight ligand-RAGE engagement as an amplifier of proinflammatory mechanisms in immune/ inflammatory diseases.…”

Section: Rage 82s Allele and Association With Rheumatoid Arthritismentioning

confidence: 99%

RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response

et al. 2002

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“…In addition advanced glycation end products may lead to damage of articular surfaces and enhance inflammation thereby contributing to osteoarthritis (39). AGEs have also been implicated in the most common form of pathologic bone loss, periodontal disease (26).…”

Section: Introductionmentioning

confidence: 99%

Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways

Alikhani

Boyd

et al. 2007

Bone

322

220

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We have previously shown that diabetes significantly enhances apoptosis of osteoblastic cells in vivo and that the enhanced apoptosis contributes to diabetes impaired new bone formation. A potential mechanism is enhanced apoptosis stimulated by advanced glycation endproducts (AGEs). To investigate this further, an advanced glycation product, carboxymethyl lysine modified collagen (CML-collagen) was injected in vivo and stimulated a 5 fold increase in calvarial periosteal cell apoptosis compared to unmodified collagen. It also induced apoptosis in primary cultures of human or neonatal rat osteoblastic cells or MC-3T3-E1 cells in vitro. Moreover, the apoptotic effect was largely mediated through RAGE receptor. CML-collagen increased p38 and JNK activity 3.2 and 4.4 fold, respectively. Inhibition of p38 and JNK reduced CML-collagen stimulated apoptosis by 45% and 59% and by 90% when used together (P<0.05). The predominant apoptotic pathway induced by CML-collagen involved caspase-8 activation of caspase-3 and was independent of NF-κB activation. When osteoblastic cells were exposed to a long-term low dose incubation with CMLcollagen there was a higher degree of apoptosis compared to short term incubation. In more differentiated osteoblastic cultures apoptosis was enhanced even further. These results indicate that advanced glycation endproducts, which accumulate in diabetic and aged individuals may promote apoptosis of osteoblastic cells and contribute to deficient bone formation.

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

Cited by 336 publications

References 54 publications

Proteolytic Degradation of VE-Cadherin Alters the Blood-Retinal Barrier in Diabetes

Proteolytic Degradation of VE-Cadherin Alters the Blood-Retinal Barrier in Diabetes

RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response

Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways

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