RAGE Signaling in Skeletal Biology
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Purpose of review The receptor for advanced glycation end products (RAGE) and several of its ligands have been implicated in the onset and progression of pathologies associated with aging, chronic inflammation, and cellular stress. In particular, the role of RAGE and its ligands in bone tissue during both physiological and pathological conditions has been investigated. However, the extent to which RAGE signaling regulates bone homeostasis and disease onset remains unclear. Further, RAGE effects in the different bone cells and whether these effects are cell-type specific is unknown. The objective of the current review is to describe the literature over RAGE signaling in skeletal biology as well as discuss the clinical potential of RAGE as a diagnostic and/or therapeutic target in bone disease.Recent findings The role of RAGE and its ligands during skeletal homeostasis, tissue repair, and disease onset/progression is beginning to be uncovered. For example, detrimental effects of the RAGE ligands, advanced glycation end products (AGEs), have been identified for osteoblast viability/activity, while others have observed that low level AGE exposure stimulates osteoblast autophagy, which subsequently promotes viability and function. Similar findings have been reported with HMGB1, another RAGE ligand, in which high levels of the ligand are associated with osteoblast/osteocyte apoptosis, whereas low level/short-term administration stimulates osteoblast differentiation/bone formation and promotes fracture healing. Additionally, elevated levels of several RAGE ligands (AGEs, HMGB1, S100 proteins) induce osteoblast/osteocyte apoptosis and stimulate cytokine production, which is associated with increased osteoclast differentiation/activity. Conversely, direct RAGE-ligand exposure in osteoclasts may have inhibitory effects. These observations support a conclusion that elevated bone resorption observed in conditions of high circulating ligands and RAGE expression are due to actions on osteoblasts/osteocytes rather than direct actions on osteoclasts, although additional work is required to substantiate the observations. Recent studies have demonstrated that RAGE and its ligands play an important physiological role in the regulation of skeletal development, homeostasis, and repair/regeneration. Conversely, elevated levels of RAGE and its ligands are clearly related with various diseases associated with increased bone loss and fragility. However, despite the recent advancements in the field, many questions regarding RAGE and its ligands in skeletal biology remain unanswered.
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RAGE is a transmembrane receptor for advanced glycosylation end products.
“In addition to the Wnt pathway, another signaling pathway implicated in the comparison of plasma profiles between flight and ground mice was that mediated by RAGE, which is a transmembrane receptor for advanced glycosylation end products (50).”
From Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight (2020) · cites this paper as [50]
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Asadipooya, K., & Uy, E. (2019) · Journal of the Endocrine Society · doi:10.1210/js.2019-00160 · Cited by 210 · see citing works
Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes
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“In addition to the Wnt pathway, another signaling pathway implicated in the comparison of plasma profiles between flight and ground mice was that mediated by RAGE, which is a transmembrane receptor for advanced glycosylation end products (50).”
Morroniside attenuates high glucose–induced BMSC dysfunction by regulating the Glo1/AGE/RAGE axis
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Biochemical Markers of Bone Fragility in Patients With Diabetes
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HGMB1 and RAGE as Essential Components of Ti Osseointegration Process in Mice
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Effects of diabetes on osteocytes
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Tripterygium Ingredients for Pathogenicity Cells in Rheumatoid Arthritis
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Hypoxia and the Receptor for Advanced Glycation End Products (RAGE) Signaling in Cancer
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Osteoclast Activation and Inflammatory Bone Diseases: Focusing on Receptors in Osteoclasts
Zhao, W., Li, J., Su, T., Wang, C., Fu, Y., Li, C., Hua, P., Liang, X., Zhu, Y., & Cui, H. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s507269 · Cited by 28 · see citing works
Biochemical Markers of Bone Turnover in Older Adults With Type 1 Diabetes
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The RAGE signaling in osteoporosis
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RAGE Signaling in Melanoma Tumors
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Engineering bone-forming callus organoid implants in a xenogeneic-free differentiation medium
Decoene, I., Herpelinck, T., Geris, L., Luyten, F. P., & Papantoniou, I. (2022) · Frontiers in Chemical Engineering · doi:10.3389/fceng.2022.892190 · Cited by 18 · see citing works
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Bone matrix quality in a developing high-fat diet mouse model is altered by RAGE deletion
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The Dramatic Role of IFN Family in Aberrant Inflammatory Osteolysis
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In vivo glycation—interplay between oxidant and carbonyl stress in bone
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Pathophysiology of Bone Fragility in Type 2 Diabetes Mellitus
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Effects of AGEs, sRAGE and HMGB1 on Clinical Outcomes in Multiple Myeloma
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- Authors
- Plotkin, L. I., Essex, A. L., & Davis, H. M.
- Affiliations
- Richard L. Roudebush VA Medical Center (US)
- Indiana University Indianapolis (US)
- Corresponding author
- Plotkin, Lilian I.
- Venue
- Current Osteoporosis Reports
- Published
- 2019-01-26
- Volume
- 17
- Issue
- 1
- Pages
- 16-25
- ISSN
- 1544-1873 (ISSN-L)
- 1544-2241
- PMC
- PMC6447316
- OpenAlex
- W2913440097
- Cited by
- 54
- References
- 97
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 4 · 2023: 6 · 2022: 11 · 2021: 5 · 2020: 10 · 2019: 4 · 2018: 1
- FWCI
- 0.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Current Osteoporosis Reports (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- PMC
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR067210, T32AR065971)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- receptor for advanced glycation end products, RAGE signaling, advanced glycation end products, HMGB1, S-100 protein, bone homeostasis, osteoblasts, osteocytes, osteoclasts, bone resorption, osteoblast apoptosis, osteogenic differentiation, fracture healing, bone fragility, bone loss, aging, chronic inflammation, skeletal development, bone regeneration
- MeSH terms
- Antigens, Neoplasm, Bone Diseases, Humans, Skeleton, Signal Transduction, Biomarkers, Mitogen-Activated Protein Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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