RAGE Signaling in Skeletal Biology
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.
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.
KeywordsRAGE Bone Osteoblast Osteoclast Osteocyte Osteoporosis
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.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 4.Zhou Z, Xiong WC. RAGE and its ligands in bone metabolism. Front Biosci (Schol Ed). 2011;3:768–76.Google Scholar
- 8.Rojas A, Morales M, Gonzalez I, Araya P. Inhibition of RAGE axis signaling: a pharmacological challenge. Curr Drug Targets. 2018. https://doi.org/10.2174/1389450119666180820105956.
- 10.Galliera E, Marazzi MG, Vianello E, Drago L, Luzzati A, Bendinelli P, et al. Circulating sRAGE in the diagnosis of osteolytic bone metastasis. J Biol Regul Homeost Agents. 2016;30:1203–8.Google Scholar
- 24.Rai V, Maldonado AY, Burz DS, Reverdatto S, Schmidt AM, Shekhtman A. Signal transduction in RAGE: solution structure of C-terminal RAGE (ctRAGE) and its binding to mDia1. J Biol Chem. 2011.Google Scholar
- 28.Ito Y, Teitelbaum SL, Zou W, Zheng Y, Johnson JF, Chappel J, et al. Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL/M-CSF signaling and osteoclast polarization. J Clin Invest. 2010;120:1981–1993.Google Scholar
- 29.•• Meng HZ, Zhang WL, Liu F, Yang MW. Advanced glycation end products affect osteoblast proliferation and function by modulating autophagy via the receptor of advanced glycation end products/Raf protein/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase (RAGE/Raf/MEK/ERK) pathway. J Biol Chem. 2015;290:28189–99. This study demonstrated that low levels of AGE-RAGE signaling stimulates autophagy and enhances osteoblast viability. CrossRefGoogle Scholar
- 52.Li S, Yang B, Teguh D, Zhou L, Xu J, Rong L. Amyloid beta peptide enhances RANKL-induced osteoclast activation through NF-kappaB, ERK, and calcium oscillation signaling. Int J Mol Sci. 2016;17.Google Scholar
- 60.Biswas S, Duttenhoefer F, Li H, Matte D, Igwe JC, Humpert PM, Kasperk C, Nawroth PP, Bierhaus A. RAGE deficiency induces a proinflammatory phenotype in bones and osteoblasts through PPAR-a suppression. 2008;3.Google Scholar
- 63.Hurtgen BJ, Ward CL, Leopold Wager CM, Garg K, Goldman SM, Henderson BEP, McKinley TO, Greising SM, Wenke JC, Corona BT. Autologous minced muscle grafts improve endogenous fracture healing and muscle strength after musculoskeletal trauma. Physiol Rep. 2017;5.Google Scholar
- 64.Taniguchi N, Yoshida K, Ito T, Tsuda M, Mishima Y, Furumatsu T, et al. Stage-specific secretion of HMGB1 in cartilage regulates endochondral ossification. Mol. Cell Biol. 2007;27:5650–63.Google Scholar
- 65.Li Q, Yu B, Yang P. Hypoxia-induced HMGB1 in would tissues promotes the osteoblast cell proliferation via activating ERK/JNK signaling. Int J Clin Exp Med. 2015;8:15087–97.Google Scholar
- 66.Franke S, Ruster C, Pester J, Hofmann G, Oelzner P, Wolf G. Advanced glycation end products affect growth and function of osteoblasts. Clin Exp Rheumatol. 2011;29:650–60.Google Scholar
- 70.• Liu J, Mao J, Jiang Y, Xia L, Mao L, Wu Y, et al. AGEs induce apoptosis in rat osteoblast cells by activating the caspase-3 signaling pathway under a high-glucose environment in vitro. Appl Biochem Biotechnol. 2016;178:1015–27. The studies in this article showed that in rat osteoblastic cells, high-glucose levels lead to AGE accumulation, which subsequently activates caspase-3 and increased apoptosis. CrossRefGoogle Scholar
- 71.•• Mao YX, Cai WJ, Sun XY, Dai PP, Li XM, Wang Q, et al. RAGE-dependent mitochondria pathway: a novel target of silibinin against apoptosis of osteoblastic cells induced by advanced glycation end products. Cell Death Dis. 2018;9:674. This study provided a new insight into the mitochondrial mechanisms that lead to AGE-induced osteoblastic cell apoptosis and identified a potential clinical use of silibinin for the prevention or treatment of diabetic osteoporosis. CrossRefGoogle Scholar
- 73.Cortizo AM, Lettieri MG, Barrio DA, Mercer N, Etcheverry SB, McCarthy AD. Advanced glycation end-products (AGEs) induce concerted changes in the osteoblastic expression of their receptor RAGE and in the activation of extracellular signal-regulated kinases (ERK). Mol Cell Biochem. 2003;250:1–10.CrossRefGoogle Scholar
- 76.Notsu M, Kanazawa I, Takeno A, Yokomoto-Umakoshi M, Tanaka KI, Yamaguchi T, et al. Advanced glycation end product 3 (AGE3) increases apoptosis and the expression of sclerostin by stimulating TGF-beta expression and secretion in osteocyte-like MLO-Y4-A2 cells. Calcif Tissue Int. 2017;100:402–11.CrossRefGoogle Scholar
- 77.•• Chen H, Liu W, Wu X, Gou M, Shen J, Wang H. Advanced glycation end products induced IL-6 and VEGF-A production and apoptosis in osteocyte-like MLO-Y4 cells by activating RAGE and ERK1/2, P38 and STAT3 signalling pathways. Int Immunopharmacol. 2017;52:143–9. This article provided evidence showing that AGEs can activate the ERK1/2, P38 and STAT3 pathways via RAGE. Additionally, AGE-induced activation of these pathways stimulates IL-6 and VEGF-A production and osteocyte apoptosis. CrossRefGoogle Scholar
- 80.•• Davis HM, Pacheco-Costa R, Atkinson EG, Brun LR, Gortazar AR, Harris J, et al. Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging. Aging Cell. 2017;16:551–63. This article showed that Cx43 and miR21 are required to maintain osteocyte survival and identified RANKL and HMGB1 as two molecules involved with elevated osteoclastogenesis. CrossRefGoogle Scholar
- 81.• Li Z, Li C, Zhou Y, Chen W, Luo G, Zhang Z, et al. Advanced glycation end products biphasically modulate bone resorption in osteoclast-like cells. Am J Physiol Endocrinol Metab. 2016;310:E355–66. This article demonstrated that AGEs biphasically modulate osteoclast activity in a differentiation stage-dependent manner. CrossRefGoogle Scholar
- 85.Yamamoto M, Yamaguchi T, Yamauchi M, Sugimoto T. Low serum level of the endogenous secretory receptor for advanced glycation end products (esRAGE) is a risk factor for prevalent vertebral fractures independent of bone mineral density in patients with type 2 diabetes. Diabetes Care. 2009;32:2263–8.CrossRefGoogle Scholar
- 87.Pullerits R, d'Elia HF, Tarkowski A, Carlsten H. The decrease of soluble RAGE levels in rheumatoid arthritis patients following hormone replacement therapy is associated with increased bone mineral density and diminished bone/cartilage turnover: a randomized controlled trial. Rheumatology (Oxford). 2009;48:785–90.CrossRefGoogle Scholar
- 89.•• Galliera E, Marazzi MG, Gazzaruso C, Gallotti P, Coppola A, Montalcini T, et al. Evaluation of circulating sRAGE in osteoporosis according to BMI, adipokines and fracture risk: a pilot observational study. Immun Ageing. 2017;14:13. This article found that serum sRAGE is associated with bone fragility, as well as, with BMI and leptin levels. These findings demonstrate the diagnostic potential sRAGE not only as a marker of osteoporosis, but also lipid metabolism status. CrossRefGoogle Scholar
- 92.Wang J, Wang H, Shi J, Ding Y. Effects of bone marrow MSCs transfected with sRAGE on the intervention of HMGB1 induced immuno-inflammatory reaction. Int J Clin Exp Pathol. 2015;8:12028–40.Google Scholar