title: ICOS-Ligand Triggering Impairs Osteoclast Differentiation and Function In Vitro and In Vivo.
abstract: Osteoblasts, osteocytes, and osteoclasts (OCs) are involved in the bone production and resorption, which are crucial in bone homeostasis. OC hyperactivation plays a role in the exaggerated bone resorption of diseases such as osteoporosis, rheumatoid arthritis, and osteolytic tumor metastases. This work stems from the finding that OCs can express B7h (ICOS-Ligand), which is the ligand of the ICOS T cell costimulatory molecule. Because recent reports have shown that, in endothelial, dendritic, and tumor cells, B7h triggering modulates several activities of these cells, we analyzed the effect of B7h triggering by recombinant ICOS-Fc on OC differentiation and function. The results showed that ICOS-Fc inhibits RANKL-mediated differentiation of human monocyte-derived OC-like cells (MDOCs) by inhibiting the acquirement of the OC morphology, the CD14-cathepsin K+phenotype, and the expression of tartrate-resistant acid phosphatase, OSCAR, NFATc1, and DC-STAMP. Moreover, ICOS-Fc induces a reversible decrease in the sizes of cells and nuclei and cathepsin K expression in mature MDOCs. Finally, ICOS-Fc inhibits the osteolytic activities of MDOCs in vitro and the development of bone loss in ovariectomized or soluble RANKL-treated mice. These findings open a novel field in the pharmacological use of agonists and antagonists of the ICOS-B7h system.
authors: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
authors: Casimiro L
authors: 0000-0002-3127-5686
authors: CL
authors: Gigliotti
authors: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
authors: Elena
authors: 0000-0003-2700-3597
authors: E
authors: Boggio
authors: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
authors: Nausicaa
authors: 0000-0002-9860-0148
authors: N
authors: Clemente
authors: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
authors: Yogesh
authors: Y
authors: Shivakumar
authors: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
authors: Erika
authors: 0000-0003-2669-6328
authors: E
authors: Toth
authors: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
authors: Daniele
authors: 0000-0003-4309-242X
authors: D
authors: Sblattero
authors: Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors: Patrizia
authors: P
authors: D'Amelio
authors: Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
authors: Giovanni C
authors: GC
authors: Isaia
authors: Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy.
authors: Chiara
authors: C
authors: Dianzani
authors: Department of Microbiology and Immunology, Tokyo Women's Medical University, Tokyo 108-8639, Japan.
authors: Junji
authors: J
authors: Yagi
authors: Departamento de Medicina Celular y Molecular, Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, 28006 Madrid, Spain; and.
authors: Josè M
authors: 0000-0001-9032-0072
authors: JM
authors: Rojo
authors: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
authors: Annalisa
authors: A
authors: Chiocchetti
authors: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy.
authors: Renzo
authors: R
authors: Boldorini
authors: Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy.
authors: Michela
authors: 0000-0002-3682-8702
authors: M
authors: Bosetti
authors: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases, University of Piemonte Orientale, 28100 Novara, Italy; umberto.dianzani@med.uniupo.it.
authors: Umberto
authors: U
authors: Dianzani
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000502:physiology; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D015202:Protein Engineering; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D000071681:Tartrate-Resistant Acid Phosphatase / Q000276:immunology
chemical_list: C498514:ICOSLG protein, human; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; C000605510:ACP5 protein, human; D000071681:Tartrate-Resistant Acid Phosphatase