title: Thrombin Cleavage of Osteopontin Modulates Its Activities in Human Cells In Vitro and Mouse Experimental Autoimmune Encephalomyelitis In Vivo.
abstract: Osteopontin is a proinflammatory cytokine and plays a pathogenetic role in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), by recruiting autoreactive T cells into the central nervous system. Osteopontin functions are modulated by thrombin cleavage generating N- and C-terminal fragment, whose individual roles are only partly known. Published data are difficult to compare since they have been obtained with heterogeneous approaches. Interestingly, thrombin cleavage of osteopontin unmasks a cryptic domain of interaction with α 4 β 1 integrin that is the main adhesion molecule involved in lymphocyte transmigration to the brain and is the target for natalizumab, the most potent drug preventing relapses. We produced recombinant osteopontin and its N- and C-terminal fragments in an eukaryotic system in order to allow their posttranslational modifications. We investigated, in vitro, their effect on human cells and in vivo in EAE. We found that the osteopontin cleavage plays a key role in the function of this cytokine and that the two fragments exert distinct effects both in vitro and in vivo. These findings suggest that drugs targeting each fragment may be used to fine-tune the pathological effects of osteopontin in several diseases.
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), "A. Avogadro" University of Piemonte Orientale (UPO), 28100 Novara, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Boggio
authors.affiliation: Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy.
authors.forename: Chiara
authors.identifier: 0000-0002-2246-3183
authors.initials: C
authors.lastname: Dianzani
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), "A. Avogadro" University of Piemonte Orientale (UPO), 28100 Novara, Italy.
authors.forename: Casimiro Luca
authors.initials: CL
authors.lastname: Gigliotti
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), "A. Avogadro" University of Piemonte Orientale (UPO), 28100 Novara, Italy.
authors.forename: Maria Felicia
authors.initials: MF
authors.lastname: Soluri
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), "A. Avogadro" University of Piemonte Orientale (UPO), 28100 Novara, Italy.
authors.forename: Nausicaa
authors.initials: N
authors.lastname: Clemente
authors.affiliation: Biocenter, Division for Experimental Pathophysiology and Immunology, Laboratory of Autoimmunity, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Giuseppe
authors.identifier: 0000-0001-5193-4688
authors.initials: G
authors.lastname: Cappellano
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), "A. Avogadro" University of Piemonte Orientale (UPO), 28100 Novara, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Toth
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), "A. Avogadro" University of Piemonte Orientale (UPO), 28100 Novara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Raineri
authors.affiliation: Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Ferrara
authors.affiliation: Department of Translational Medicine, Neurology Unit, "A. Avogadro" UPO, 28100 Novara, Italy.
authors.forename: Cristoforo
authors.identifier: 0000-0002-6862-9468
authors.initials: C
authors.lastname: Comi
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), "A. Avogadro" University of Piemonte Orientale (UPO), 28100 Novara, Italy.
authors.forename: Umberto
authors.identifier: 0000-0001-6723-3931
authors.initials: U
authors.lastname: Dianzani
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), "A. Avogadro" University of Piemonte Orientale (UPO), 28100 Novara, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiocchetti
mesh_terms: D000818:Animals; D015415:Biomarkers; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D059748:Proteolysis; D011994:Recombinant Proteins; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D010446:Peptide Fragments; D011994:Recombinant Proteins; D053495:Osteopontin; D013917:Thrombin