Molecular and Cellular Biochemistry

, Volume 306, Issue 1–2, pp 87–94 | Cite as

Regulation of advanced glycation end product (AGE) receptors and apoptosis by AGEs in osteoblast-like cells

  • Natalia Mercer
  • Hafiz Ahmed
  • Susana B. Etcheverry
  • Gerardo R. Vasta
  • Ana Maria Cortizo


Advanced glycation end products (AGEs) have been proposed as the pathological mechanisms underlying diabetic chronic complications. They may also play a role in the pathogenesis of diabetic osteopenia, although their mechanisms of action remain unclear. We investigated the protein (immunofluorescence) and gene expression (realtime RT-PCR) of two receptors for AGEs, RAGE and galectin-3, as well as their regulation by AGEs, and the apoptotic effect on osteoblast-like cells (UMR106 and MC3T3E1) in culture. AGEs up-regulated the expression of RAGE and galectin-3 in both cells lines. These effects were accompanied by an increase in the corresponding mRNA in the non-tumoral MC3T3E1 but not in the osteosarcoma UMR106 cells. Finally, we demonstrated that a 24 h exposure to AGEs induced apoptosis in both cell lines. Thus, AGEs-receptors may play important roles in the bone alterations described in aging and diabetic patients.


Advanced glycation end products RAGE Galectin-3 Osteoblasts Apoptosis AGE-receptors Regulation 



This work was partially supported by grants from Universidad Nacional de La Plata, Ministerio de Salud y Acción Social de la Nación (Subsecretaría de Investigación y Tecnología, Beca Ramón Carrillo-Arturo Oñativia) and CICPBA to AMC, and grant R01 GM070589-01 from the NIGMS, National Institutes of Health to GRV. NM is a fellow of CONICET, SBE is a member of the Carrera del Investigador, CONICET, and AMC is a member of the Carrera del Investigador, CICPBA.


  1. 1.
    Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820PubMedCrossRefGoogle Scholar
  2. 2.
    Vlassara H (1997) Recent progress in advanced glycation end products and diabetic complications. Diabetes 46(Suppl 2):S19–S25PubMedGoogle Scholar
  3. 3.
    Thornalley PJ (1998) Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs. Cell Mol Biol (Noisy-le-grand) 44:1013–1023Google Scholar
  4. 4.
    Schmidt AM, Yan SD, Yan SF, Stern DM (2000) The biology of the receptor for advanced glycation end products and its ligands. Biochim Biophys Acta 1498:99–111PubMedCrossRefGoogle Scholar
  5. 5.
    Liu F-T, Patterson RJ, Wang JL (2002) Intracellular functions of galectins. Biochim Biophys Acta 1572:263–273PubMedGoogle Scholar
  6. 6.
    Vashishth D, Gibson GJ, Khoury JI et al (2001) Influence of nonenzymatic glycation on biomechanical properties of cortical bone. Bone 28:195–201PubMedCrossRefGoogle Scholar
  7. 7.
    Alikhani Z, Alikhani M, Boyd CM et al (2005) Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways. J Biol Chem 280:12087–12095PubMedCrossRefGoogle Scholar
  8. 8.
    Chen BH, Jiang DY, Tang LS (2006) Advanced glycation end-products induce apoptosis involving the signaling pathways of oxidative stress in bovine retinal pericytes. Life Sci 79:1040–1048PubMedCrossRefGoogle Scholar
  9. 9.
    Alikhani M, Alikhani Z, Boyd C et al (2007) Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone 40:345–353PubMedCrossRefGoogle Scholar
  10. 10.
    Kume S, Kato S, Yamagishi S et al (2005) Advanced glycation end-products attenuate human mesenchymal stem cells and prevent cognate differentiation into adipose tissue, cartilage, and bone. J Bone Miner Res 20:1647–1658PubMedCrossRefGoogle Scholar
  11. 11.
    Yatoh S, Mizutani M, Yokoo T et al (2006) Antioxidants and an inhibitor of advanced glycation ameliorate death of retinal microvascular cells in diabetic retinopathy. Diabetes Metab Res Rev 22:38–45PubMedCrossRefGoogle Scholar
  12. 12.
    McCarthy AD, Etcheverry SB, Bruzzone L, Cortizo AM (1997) Effects of advanced glycation end-products on the proliferation and differentiation of osteoblast-like cells. Mol Cell Biochem 170:43–51PubMedCrossRefGoogle Scholar
  13. 13.
    McCarthy AD, Etcheverry SB, Bruzzone L et al (2001) Non-enzymatic glycosylation of a type I collagen matrix: effects on osteoblastic development and oxidative stress. BMC Cell Biol 2:16PubMedCrossRefGoogle Scholar
  14. 14.
    McCarthy AD, Etcheverry SB, Cortizo AM (1999) Advanced glycation endproduct-specific receptors in rat and mouse osteoblast-like cells: regulation with stages of differentiation. Acta Diabetol 36:45–52PubMedCrossRefGoogle Scholar
  15. 15.
    McCarthy AD, Etcheverry SB, Cortizo AM (2001) Effect of advanced glycation endproducts on the secretion of insulin-like growth factor-I and its binding proteins: role in osteoblast development. Acta Diabetol 38:113–122PubMedCrossRefGoogle Scholar
  16. 16.
    Cortizo AM, Lettieri MG, Barrio DA et al (2003) Advanced glycation endproducts (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 250:1–10PubMedCrossRefGoogle Scholar
  17. 17.
    Mercer N, Ahmed H, McCarthy AD et al (2004) AGE-R3/galectin-3 expression in osteoblast-like cells: regulation by AGEs. Mol Cell Biochem 266:17–24PubMedCrossRefGoogle Scholar
  18. 18.
    Partridge NC, Alcorn D, Michelangeli VP et al (1983) Morphological and biochemical characterization of four clonal osteogenic sarcoma cell lines of rat origin. Cancer Res 43:4308–4312PubMedGoogle Scholar
  19. 19.
    Quarles LD, Yahay DA, Lever LW et al (1992) Distinct proliferative and differentiated stages of murine MC3T3E1 cells in culture: an in vitro model of osteoblast development. J Bone Miner Res 7:683–692PubMedCrossRefGoogle Scholar
  20. 20.
    Molinuevo MS, Barrio DA, Cortizo AM, Etcheverry SB (2004) Antitumoral properties of two new vanadyl(IV) complexes on osteoblasts in culture. Role of apoptosis and oxidative stress. Cancer Chemother Pharmacol 53:163–172PubMedCrossRefGoogle Scholar
  21. 21.
    Forbes JM, Cooper ME, Thallas V et al (2002) Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy. Diabetes 51:3274–3282PubMedCrossRefGoogle Scholar
  22. 22.
    Ding KH, Wang ZZ, Hamrick MW et al (2006) Disordered osteoclast formation in RAGE-deficient mouse establishes an essential role for RAGE in diabetes related bone loss. Biochem Biophys Res Commun 340:1091–1097PubMedCrossRefGoogle Scholar
  23. 23.
    Hein G, Weiss C, Lehmann G et al (2006) Advanced glycation end product modification of bone proteins and bone remodeling: hypothesis and preliminary immunohistological findings. Ann Rheum Dis 65:101–104PubMedCrossRefGoogle Scholar
  24. 24.
    Odetti P, Rossi S, Monacelli F et al (2005) Advanced glycation end products and bone loss during aging. Ann N Y Acad Sci 1043:710–717PubMedCrossRefGoogle Scholar
  25. 25.
    Vlassara H, Li YM, Imani F et al (1995) Identification of galectin-3 as a high-affinity binding protein for advanced glycation end products (AGE): a new member of the AGE-receptor complex. Mol Med 1:634–646PubMedGoogle Scholar
  26. 26.
    Pugliese G, Pricci F, Leto G et al (2000) The diabetic milieu modulates the advanced glycation end product-receptor complex in the mesangium by inducing or upregulating galectin-3 expression. Diabetes 49:1249–1257PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Natalia Mercer
    • 1
  • Hafiz Ahmed
    • 2
  • Susana B. Etcheverry
    • 1
  • Gerardo R. Vasta
    • 2
  • Ana Maria Cortizo
    • 1
  1. 1.Cátedra de Bioquímica Patológica, Facultad de Ciencias ExactasUniversidad Nacional de La PlataLa PlataArgentina
  2. 2.Center of Marine BiotechnologyUniversity of Maryland Biotechnology InstituteBaltimoreUSA

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