title: Galectin-1 Couples Glycobiology to Inflammation in Osteoarthritis through the Activation of an NF-κB-Regulated Gene Network.
abstract: Osteoarthritis is a degenerative joint disease that ranks among the leading causes of adult disability. Mechanisms underlying osteoarthritis pathogenesis are not yet fully elucidated, putting limits to current disease management and treatment. Based on the phenomenological evidence for dysregulation within the glycome of chondrocytes and the network of a family of adhesion/growth-regulatory lectins, that is, galectins, we tested the hypothesis that Galectin-1 is relevant for causing degeneration. Immunohistochemical analysis substantiated that Galectin-1 upregulation is associated with osteoarthritic cartilage and subchondral bone histopathology and severity of degeneration (p < 0.0001, n = 29 patients). In vitro, the lectin was secreted and it bound to osteoarthritic chondrocytes inhibitable by cognate sugar. Glycan-dependent Galectin-1 binding induced a set of disease markers, including matrix metalloproteinases and activated NF-κB, hereby switching on an inflammatory gene signature (p < 10(-16)). Inhibition of distinct components of the NF-κB pathway using dedicated inhibitors led to dose-dependent impairment of Galectin-1-mediated transcriptional activation. Enhanced secretion of effectors of degeneration such as three matrix metalloproteinases underscores the data's pathophysiological relevance. This study thus identifies Galectin-1 as a master regulator of clinically relevant inflammatory-response genes, working via NF-κB. Because inflammation is critical to cartilage degeneration in osteoarthritis, this report reveals an intimate relation of glycobiology to osteoarthritic cartilage degeneration.
authors.affiliation: Karl Chiari Lab for Orthopaedic Biology, Department of Orthopaedics, Medical University of Vienna, 1090 Vienna, Austria; stefan.toegel@meduniwien.ac.at.
authors.forename: Stefan
authors.initials: S
authors.lastname: Toegel
authors.affiliation: Karl Chiari Lab for Orthopaedic Biology, Department of Orthopaedics, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Daniela
authors.initials: D
authors.lastname: Weinmann
authors.affiliation: Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians-University Munich, 80539 Munich, Germany;
authors.forename: Sabine
authors.initials: S
authors.lastname: André
authors.affiliation: Karl Chiari Lab for Orthopaedic Biology, Department of Orthopaedics, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Walzer
authors.affiliation: Department of Laboratory Medicine and Core Facility Genomics, Core Facilities, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.affiliation: Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians-University Munich, 80539 Munich, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Karl Chiari Lab for Orthopaedic Biology, Department of Orthopaedics, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Catharina
authors.initials: C
authors.lastname: Chiari
authors.affiliation: Karl Chiari Lab for Orthopaedic Biology, Department of Orthopaedics, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Reinhard
authors.initials: R
authors.lastname: Windhager
authors.affiliation: Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University Vienna, 1090 Vienna, Austria; and.
authors.forename: Christoph
authors.initials: C
authors.lastname: Krall
authors.affiliation: B2 Scientific Group, 1180 Vienna, Austria.
authors.forename: Idriss M
authors.initials: IM
authors.lastname: Bennani-Baiti
authors.affiliation: Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians-University Munich, 80539 Munich, Germany;
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gabius
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D037483:Galectin 1 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D053263:Gene Regulatory Networks / Q000502:physiology*; D054794:Glycomics; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D037483:Galectin 1; D016328:NF-kappa B