title: The galectin-3/RAGE dyad modulates vascular osteogenesis in atherosclerosis.
abstract: OBJECTIVE
  Vascular calcification correlates with inflammation and plaque instability in a dual manner, depending on the spotty/granular (micro) or sheet-like/lamellated (macro) pattern of calcification. Modified lipoproteins trigger both inflammation and calcification via receptors for advanced lipoxidation/glycation endproducts (ALEs/AGEs). This study compared the roles of galectin-3 and receptor for AGEs (RAGE), two ALEs/AGEs-receptors with diverging effects on inflammation and bone metabolism, in the process of vascular calcification.
  
  
  RESULTS
  We evaluated galectin-3 and RAGE expression/localization in 62 human carotid plaques and its relation to calcification pattern, plaque phenotype, and markers of inflammation and vascular osteogenesis; and the effect of galectin-3 ablation and/or exposure to an ALE/AGE on vascular smooth muscle cell (VSMC) osteogenic differentiation. While RAGE co-localized with inflammatory cells in unstable regions with microcalcification, galectin-3 was expressed also by VSMCs, especially in macrocalcified areas, where it co-localized with alkaline phosphatase. Expression of galectin-3 and osteogenic markers was higher in macrocalcified plaques, whereas the opposite occurred for RAGE and inflammatory markers. Galectin-3-deficient VSMCs exhibited defective osteogenic differentiation, as shown by altered expression of osteogenic transcription factors and proteins, blunted activation of pro-osteoblastogenic Wnt/β-catenin signalling and proliferation, enhanced apoptosis, and disorganized mineralization. These abnormalities were associated with RAGE up-regulation, but were only in part prevented by RAGE silencing, and were partially mimicked or exacerbated by treatment with an AGE/ALE.
  
  
  CONCLUSIONS
  These data indicate a novel molecular mechanism by which galectin-3 and RAGE modulate in divergent ways, not only inflammation, but also vascular osteogenesis, by modulating Wnt/β-catenin signalling, and independently of ALEs/AGEs.
authors: Department of Clinical and Molecular Medicine, 'La Sapienza' University, Via di Grottarossa, 1035-1039, 00189, Rome, Italy.
authors: Stefano
authors: S
authors: Menini
authors: Carla
authors: C
authors: Iacobini
authors: Carlo
authors: C
authors: Ricci
authors: Claudia
authors: C
authors: Blasetti Fantauzzi
authors: Laura
authors: L
authors: Salvi
authors: Carlo M
authors: CM
authors: Pesce
authors: Michela
authors: M
authors: Relucenti
authors: Giuseppe
authors: G
authors: Familiari
authors: Maurizio
authors: M
authors: Taurino
authors: Giuseppe
authors: G
authors: Pugliese
mesh_terms: D000368:Aged; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001798:Blood Proteins; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D016893:Carotid Stenosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D037502:Galectin 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D037161:Galectins; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis; D018384:Oxidative Stress; D058226:Plaque, Atherosclerotic; D034622:RNA Interference; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D061205:Vascular Calcification / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D060449:Wnt Signaling Pathway
chemical_list: D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; D017127:Glycation End Products, Advanced; D018836:Inflammation Mediators; C428445:LGALS3 protein, human; C485095:Lgals3 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000469:Alkaline Phosphatase
keywords: Galectin-3; Inflammation; RAGE; Vascular calcification; Wnt/β-catenin