title: INF-γ encoding plasmid administration triggers bone loss and disrupts bone marrow microenvironment.
abstract: IFN-γ is a pleotropic cytokine produced in the bone microenvironment. Although IFN-γ is known to play a critical role on bone remodeling, its function is not fully elucidated. Consistently, outcomes on the effects of IFN-γ recombinant protein on bone loss are contradictory among reports. In our work we explored, for the first time, the role of IFN-γ encoding plasmid (pIFN-γ) in a mouse model of osteopenia induced by ovariectomy and in the sham-operated counterpart to estimate its effects in skeletal homeostasis. Ovariectomy produced a dramatic decrease of bone mineral density (BMD). pINF-γ injected mice showed a pathologic bone and bone marrow phenotype; the disrupted cortical and trabecular bone microarchitecture was accompanied by an increased release of pro-inflammatory cytokine by bone marrow cells. Moreover, mesenchymal stem cells' (MSCs) commitment to osteoblast was found impaired, as evidenced by the decline of osterix-positive (Osx+) cells within the mid-diaphyseal area of femurs. For instance, a reduction and redistribution of CXCL12 cells have been found, in accordance with bone marrow morphological alterations. As similar effects were observed both in sham-operated and in ovariectomized mice, our studies proved that an increased IFN-γ synthesis in bone marrow might be sufficient to induce inflammatory and catabolic responses even in the absence of pathologic predisposing substrates. In addition, the obtained data might raise questions about pIFN-γ's safety when it is used as vaccine adjuvant.
authors.affiliation: School of Bioscience and Veterinary MedicineUniversity of Camerino, Camerino, Italy.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Agas
authors.affiliation: Departamento de Bioquímica e ImunologiaUniversidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Gusmão Silva
authors.affiliation: School of Bioscience and Veterinary MedicineUniversity of Camerino, Camerino, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Laus
authors.affiliation: School of Bioscience and Veterinary MedicineUniversity of Camerino, Camerino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Marchegiani
authors.affiliation: School of Bioscience and Veterinary MedicineUniversity of Camerino, Camerino, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Capitani
authors.affiliation: School of Bioscience and Veterinary MedicineUniversity of Camerino, Camerino, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Vullo
authors.affiliation: School of Bioscience and Veterinary MedicineUniversity of Camerino, Camerino, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Catone
authors.affiliation: School of Bioscience and Veterinary MedicineUniversity of Camerino, Camerino, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lacava
authors.affiliation: School of Bioscience and Veterinary MedicineUniversity of Camerino, Camerino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Concetti
authors.affiliation: School of Bioscience and Veterinary MedicineUniversity of Camerino, Camerino, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchetti
authors.affiliation: School of Bioscience and Veterinary MedicineUniversity of Camerino, Camerino, Italy giovanna.sabbieti@unicam.it.
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Sabbieti
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D001851:Bone Diseases, Metabolic / Q000378:metabolism / Q000473:pathology*; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016723:Bone Remodeling / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D007371:Interferon-gamma / Q000008:administration & dosage*; D051379:Mice; D010052:Ovariectomy
chemical_list: D007371:Interferon-gamma
keywords: INF-γ; bone loss; bone marrow; plasmid DNA