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Review
. 2019 Jul 10;3(10):1799-1818.
doi: 10.1210/js.2019-00160. eCollection 2019 Oct 1.

Advanced Glycation End Products (AGEs), Receptor for AGEs, Diabetes, and Bone: Review of the Literature

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Free PMC article
Review

Advanced Glycation End Products (AGEs), Receptor for AGEs, Diabetes, and Bone: Review of the Literature

Kamyar Asadipooya et al. J Endocr Soc. .
Free PMC article

Abstract

Diabetes compromises bone cell metabolism and function, resulting in increased risk of fragility fracture. Advanced glycation end products (AGEs) interact with the receptor for AGEs (RAGE) and can make a meaningful contribution to bone cell metabolism and/or alter function. Searches in PubMed using the key words "advanced glycation end-product," "RAGE," "sRAGE," "bone," and "diabetes" were made to explain some of the clinical outcomes of diabetes in bone metabolism through the AGE-RAGE signaling pathway. All published clinical studies were included in tables. The AGE-RAGE signaling pathway participates in diabetic complications, including diabetic osteopathy. Some clinical results in diabetic patients, such as reduced bone density, suppressed bone turnover markers, and bone quality impairment, could be potentially due to AGE-RAGE signaling consequences. However, the AGE-RAGE signaling pathway has some helpful roles in the bone, including an increase in osteogenic function. Soluble RAGE (sRAGE), as a ligand decoy, may increase in either conditions of RAGE production or destruction, and then it cannot always reflect the AGE-RAGE signaling. Recombinant sRAGE can block the AGE-RAGE signaling pathway but is associated with some limitations, such as accessibility to AGEs, an increase in other RAGE ligands, and a long half-life (24 hours), which is associated with losing the beneficial effect of AGE/RAGE. As a result, sRAGE is not a helpful marker to assess activity of the RAGE signaling pathway. The recombinant sRAGE cannot be translated into clinical practice due to its limitations.

Keywords: RAGE; advanced glycation end product; diabetes; osteoporosis.

Conflict of interest statement

Disclosure Summary: The authors have nothing to disclose.All data generated or analyzed during this study are included in this published article or in the data repositories listed in References and Notes.

Figures

Figure 1.
Figure 1.
Formation of AGEs, induction of RAGE (a), and sRAGE production (b). (a) The three different pathways leading to the formation of endogenous AGEs consist of the Maillard reaction, the polyol pathway, and lipid peroxidation. Reducing sugar (glucose, fructose, glyceraldehyde) or reactive dicarbonyl compounds (products of lipid peroxidation) reacts with the macromolecules (such as the amino group of proteins), and then, after the modification process, results in the production of AGEs. Advanced lipoxidation end products (ALEs) are produced by reactive dicarbonyl compounds, which are generated by lipid peroxidation. Polyunsaturated fatty acids (membrane lipids) will produce reactive carbonyl species after being damaged by ROS and further oxidation. Additional modification of ALEs can advance AGE production unless the detoxification becomes dominant. A daily diet including high fat, high sugar, alcohol, and processed foods are important sources of the AGEs. (b) sRAGE production through enzymatic cleavage of external of the RAGE [6, 7, 11]. LPA, lysophosphatidic acid; MMP, matrix metalloproteinase.
Figure 2.
Figure 2.
The process of development and function of AGE–RAGE signaling [, , , , , –64, 79].
Figure 3.
Figure 3.
Diverse strategies to target RAGE function and expression.

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