Use of Topical sRAGE in Diabetic Wounds Increases Neovascularization and Granulation Tissue Formation

Wear-Maggitti, Kelley; Lee, James; Conejero, Alejandro Ríos; Schmidt, Annemarie; Grant, Robert Jason; Breitbart, Arnold S.

doi:10.1097/01.sap.0000122857.49274.8c

Cited by 43 publications

(24 citation statements)

References 12 publications

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“…Notably, treatment of the RAGE knockout mice with sRAGE offered no protection against asbestos-induced pulmonary fibrosis despite seeing the protein in the lung. This is in contrast to other RAGErelated disease processes, including atherosclerosis 25 and wound healing, 44 in which this dosage of sRAGE prevented disease. This suggests that the absence of mRAGE in the knockout mice may be the primary mediator contributing to pulmonary fibrosis in these mice.…”

Section: Discussionmentioning

confidence: 85%

A Role for the Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis

Englert

Hanford

Kaminski

et al. 2008

The American Journal of Pathology

209

220

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Idiopathic pulmonary fibrosis (IPF) is a severely debilitating disease associated with a dismal prognosis. There are currently no effective therapies for IPF, thus the identification of novel therapeutic targets is greatly needed. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptors whose activation has been linked to various pathologies. In healthy adult animals, RAGE is expressed at the highest levels in the lung compared to other tissues. To investigate the hypothesis that RAGE is involved in IPF pathogenesis, we have examined its expression in two mouse models of pulmonary fibrosis and in human tissue from IPF patients. In each instance we observed a depletion of membrane RAGE and its soluble (decoy) isoform, sRAGE, in fibrotic lungs. In contrast to other diseases in which RAGE signaling promotes pathology, immunohistochemical and hydroxyproline quantification studies on aged RAGEnull mice indicate that these mice spontaneously develop pulmonary fibrosis-like alterations. Furthermore, when subjected to a model of pulmonary fibrosis, RAGE-null mice developed more severe fibrosis, as measured by hydroxyproline assay and histological scoring, than wild-type controls. Combined with data from other studies on mouse models of pulmonary fibrosis and human IPF tissues indicate that loss of RAGE contributes to IPF pathogenesis. Idiopathic pulmonary fibrosis (IPF) is a debilitating disease with a dismal prognosis. Mean survival time after biopsy-confirmed diagnosis is 3 to 5 years.1,2 Traditional therapy involves the use of corticosteroids as nonspecific anti-inflammatory agents. This treatment produces an objective response in only 10 to 20% of patients and has a minimal effect on the fatal course of IPF.2-4 Thus, the need for new therapeutic modalities is evident.The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin super family of cell surface receptors. 5 In most healthy adult animal tissues, RAGE is expressed at low to undetectable levels.6,7 Activation of membrane-bound RAGE (mRAGE) by its ligands (including advanced glycation end products, HMGB1/amphoterin, S100/calgranulins, and amyloid-␤ peptide) often leads to proinflammatory signaling as well as up-regulation of RAGE itself.8 This signaling by mRAGE is believed to play an important role in disease progression for several nonpulmonary diseases, including various diabetic complications, chronic inflammation, and Alzheimer's disease, among others. 9,10 In contrast to other healthy adult tissues, RAGE mRNA and sRAGE protein are highly expressed in normal adult lungs. 6,7,11 Most recently it has been suggested that RAGE is a marker of type I alveolar epithelial cells 12 and type II alveolar epithelial cell transdifferentiation, a component of pulmonary re-epithelialization and repair.

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Section: Discussionmentioning

confidence: 85%

A Role for the Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis

Englert

Hanford

Kaminski

et al. 2008

The American Journal of Pathology

209

220

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“…sRAGE, a synthetic version of a naturally occurring secreted form of the receptor that sequesters RAGE ligands, has been most studied in this regard. Administration of sRAGE was shown to suppress the growth of tumor cells in animal studies (6), improve outcomes in diabetes (11, 12), and block the transport of amyloid-β across the blood-brain barrier (13). These preclinical studies support the hypothesis that blocking RAGE activation will be useful as a treatment in a variety of pathologies.…”

Section: Introductionmentioning

confidence: 99%

S100P-Derived RAGE Antagonistic Peptide Reduces Tumor Growth and Metastasis

Arumugam

Ramachandran

Gomez

et al. 2012

Clinical Cancer Research

137

115

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Purpose: The receptor for advanced glycation end products (RAGE) contributes to multiple pathologies, including diabetes, arthritis, neurodegenerative diseases, and cancer. Despite the obvious need, no RAGE inhibitors are in common clinical use. Therefore, we developed a novel small RAGE antagonist peptide (RAP) that blocks activation by multiple ligands.Experimental Design: RAGE and its ligands were visualized by immunohistochemical analysis of human pancreatic tissues, and siRNA was used to analyze their functions. Interactions between RAGE and S100P, S100A4, and HMGB-1 were measured by ELISA. Three S100P-derived small antagonistic peptides were designed, synthesized, and tested for inhibition of RAGE binding. The effects of the peptide blockers on NFkB-luciferase reporter activity was used to assess effects on RAGE-mediated signaling. The most effective peptide was tested on glioma and pancreatic ductal adenocarcinoma (PDAC) models.Results: Immunohistochemical analysis confirmed the expression of RAGE and its ligands S100P, S100A4, and HMGB-1 in human PDAC. siRNA silencing of RAGE or its ligands reduced the growth and migration of PDAC cells in vitro. The most effective RAP inhibited the interaction of S100P, S100A4, and HMGB-1 with RAGE at micromolar concentrations. RAP also reduced the ability of the ligands to stimulate RAGE activation of NFkB in cancer cells in vitro and in vivo. Importantly, systemic in vivo administration of RAP reduced the growth and metastasis of pancreatic tumors and also inhibited glioma tumor growth.Conclusion: RAP shows promise as a tool for the investigation of RAGE function and as an in vivo treatment for RAGE-related disorders.

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“…Soluble RAGE lacks the transmembrane domain, and is therefore released into the extracellular space. Since soluble RAGE retains the V-type domain, which is believed to be the principal site for ligand binding, soluble RAGE acts as a decoy receptor for RAGE ligands, inhibiting the activation of full-length RAGE by sequestering the RAGE ligands prior to their interaction with the RAGE receptor [Park et al, 1998;Thornalley, 1998;Schmidt et al, 2000Schmidt et al, , 2001 Bucciarelli et al, 2002a,b;Wear-Maggitti et al, 2004]. The least characterized form of RAGE is DNRAGE.…”

mentioning

confidence: 97%

“…This model proposes that S100 might increase the production of soluble RAGE from the osteoblastic cells. Among the six isoforms for RAGE, soluble RAGE has been shown to be able to suppress full-length RAGE activation by sequestering RAGE ligands before they encounter the membrane form of RAGE [Park et al, 1998;Bucciarelli et al, 2002a;Wear-Maggitti et al, 2004]. Hanford et al [2004] reported that soluble RAGE results from an alternative splicing of RAGE mRNA in humans, but soluble RAGE in the mouse results from a carboxyl-terminal truncation, suggesting that soluble RAGE isoform production would not be distinguishable from full-length RAGE at the level of mRNA expression.…”

mentioning

confidence: 97%

Direct inhibitory and indirect stimulatory effects of RAGE ligand S100 on sRANKL‐induced osteoclastogenesis

Yoshida

Flegler

Kozlov

et al. 2009

J of Cellular Biochemistry

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Diabetes results in increased fracture risk, and advance glycation endproducts (AGEs) have been implicated in this pathophysiology. S100 proteins are ligands for the receptor of AGEs (RAGE). An intracellular role of the S100 family member S100A4 (Mts1) to suppress mineralization has been described in pre-osteoblastic MC3T3-E1 cells. However, S100 proteins could have additional effects on bone. The goal of the current study was to determine effects of increased extracellular S100 on osteoclastogenesis. We first determined the direct effects of S100 on pre-osteoclast proliferation and osteoclastic differentiation. RANKL-treated RAW 264.7 cell proliferation and TRAP activity were significantly inhibited by S100, and the number and size of TRAP-positive multinucleated cells were decreased. We then determined whether S100 could affect osteoclastogenesis by an indirect process by examining effects of conditioned media from S100-treated MC3T3-E1 cells on osteoclastogenesis. In contrast to the direct inhibitory effect of S100, the conditioned media promoted RAW 264.7 cell proliferation and TRAP activity, with a trend toward increased TRAP-positive multinucleated cells. S100 treatment of the MC3T3-E1 cells for 14 days did not significantly affect alkaline phosphatase, M-CSF, or OPG gene expression. RANKL was undetectable in both untreated and treated cells. The treatment slightly decreased MC3T3-E1 cell proliferation. Interestingly, S100 treatment increased expression of RAGE by the MC3T3-E1 cells. This suggested the possibility that S100 could increase soluble RAGE, which acts as a decoy receptor for S100. This decrease in availability of S100, an inhibitor of pre-osteoclast proliferation, could contribute to osteoclastogenesis, ultimately resulting in increased bone resorption.

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Use of Topical sRAGE in Diabetic Wounds Increases Neovascularization and Granulation Tissue Formation

Cited by 43 publications

References 12 publications

A Role for the Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis

A Role for the Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis

S100P-Derived RAGE Antagonistic Peptide Reduces Tumor Growth and Metastasis

Direct inhibitory and indirect stimulatory effects of RAGE ligand S100 on sRANKL‐induced osteoclastogenesis

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