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Current Osteoporosis Reports

, Volume 17, Issue 1, pp 16–25 | Cite as

RAGE Signaling in Skeletal Biology

  • Lilian I. PlotkinEmail author
  • Alyson L. Essex
  • Hannah M. Davis
Skeletal Biology and Regulation (M Forwood and A Robling, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Skeletal Biology and Regulation

Abstract

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.

Summary

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.

Keywords

RAGE Bone Osteoblast Osteoclast Osteocyte Osteoporosis 

Notes

Funding Information

This research was supported by the National Institutes of Health R01-AR067210 to LIP. HMD is supported by an NIH T32-AR065971 grant and by the 2018 Cagiantas Scholarship from the Indiana University School of Medicine. ALE is supported by an NIH T32-AR065971 grant.

Compliance with Ethical Standards

Conflict of Interest

Lillian Plotkin, Alyson Essex, and Hannah Davis declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Lilian I. Plotkin
    • 1
    • 2
    • 3
    Email author
  • Alyson L. Essex
    • 1
    • 3
  • Hannah M. Davis
    • 1
    • 3
  1. 1.Department of Anatomy and Cell BiologyIndiana University School of MedicineIndianapolisUSA
  2. 2.Roudebush Veterans Administration Medical CenterIndianapolisUSA
  3. 3.Indiana Center for Musculoskeletal HealthIndianapolisUSA

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