title: Galectin-3 Induces a Pro-degradative/inflammatory Gene Signature in Human Chondrocytes, Teaming Up with Galectin-1 in Osteoarthritis Pathogenesis.
abstract: Inflammatory chemo- and cytokines and matrix-degrading proteases underlie the progression of osteoarthritis (OA). Aiming to define upstream regulators for these disease markers, we pursued initial evidence for an upregulation of members of the adhesion/growth-regulatory galectin family. Immunohistochemical localization of galectin-3 (Gal-3) in sections of human cartilage with increasing levels of degeneration revealed a linear correlation reaching a chondrocyte positivity of 60%. Presence in situ was cytoplasmic, the lectin was secreted from OA chondrocytes in culture and binding of Gal-3 yielded lactose-inhibitable surface staining. Exposure of cells to the lectin led to enhanced gene expression and secretion of functional disease markers. Genome-wide transcriptomic analysis broadened this result to reveal a pro-degradative/inflammatory gene signature under the control of NF-κB. Fittingly, targeting this route of activation by inhibitors impaired the unfavourable response to Gal-3 binding, as also seen by shortening the lectin's collagen-like repeat region. Gal-3's activation profile overlaps with that of homodimeric galectin-1 (Gal-1) and also has distinctive (supplementing) features. Tested at subsaturating concentrations in a mixture, we found cooperation between the two galectins, apparently able to team up to promote OA pathogenesis. In summary, our results suggest that a network of endogenous lectins is relevant for initiating this process cascade.
authors.affiliation: Karl Chiari Lab for Orthopaedic Biology, Department of Orthopaedics, Medical University of Vienna, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Weinmann
authors.affiliation: Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Schlangen
authors.affiliation: Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians-University Munich, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: André
authors.affiliation: Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians-University 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, Austria.
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Walzer
authors.affiliation: Karl Chiari Lab for Orthopaedic Biology, Department of Orthopaedics, Medical University of Vienna, Austria.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kubista
authors.affiliation: Karl Chiari Lab for Orthopaedic Biology, Department of Orthopaedics, Medical University of Vienna, Austria.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Windhager
authors.affiliation: Karl Chiari Lab for Orthopaedic Biology, Department of Orthopaedics, Medical University of Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Toegel
authors.affiliation: Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians-University Munich, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gabius
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001798:Blood Proteins; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D037483:Galectin 1 / Q000378:metabolism*; D037502:Galectin 3 / Q000378:metabolism*; D037161:Galectins; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010003:Osteoarthritis / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D015398:Signal Transduction
chemical_list: D001798:Blood Proteins; D037483:Galectin 1; D037502:Galectin 3; D037161:Galectins; C445499:LGALS1 protein, human; C428445:LGALS3 protein, human