title: MHC class II transactivator is an in vivo regulator of osteoclast differentiation and bone homeostasis co-opted from adaptive immunity.
abstract: The molecular networks controlling bone homeostasis are not fully understood. The common evolution of bone and adaptive immunity encourages the investigation of shared regulatory circuits. MHC Class II Transactivator (CIITA) is a master transcriptional co-activator believed to be exclusively dedicated for antigen presentation. CIITA is expressed in osteoclast precursors, and its expression is accentuated in osteoporotic mice. We thus asked whether CIITA plays a role in bone biology. To this aim, we fully characterized the bone phenotype of two mouse models of CIITA overexpression, respectively systemic and restricted to the monocyte-osteoclast lineage. Both CIITA-overexpressing mouse models revealed severe spontaneous osteoporosis, as assessed by micro-computed tomography and histomorphometry, associated with increased osteoclast numbers and enhanced in vivo bone resorption, whereas osteoblast numbers and in vivo bone-forming activity were unaffected. To understand the underlying cellular and molecular bases, we investigated ex vivo the differentiation of mutant bone marrow monocytes into osteoclasts and immune effectors, as well as osteoclastogenic signaling pathways. CIITA-overexpressing monocytes differentiated normally into effector macrophages or dendritic cells but showed enhanced osteoclastogenesis, whereas CIITA ablation suppressed osteoclast differentiation. Increased c-fms and receptor activator of NF-κB (RANK) signaling underlay enhanced osteoclast differentiation from CIITA-overexpressing precursors. Moreover, by extending selected phenotypic and cellular analyses to additional genetic mouse models, namely MHC Class II deficient mice and a transgenic mouse line lacking a specific CIITA promoter and re-expressing CIITA in the thymus, we excluded MHC Class II expression and T cells from contributing to the observed skeletal phenotype. Altogether, our study provides compelling genetic evidence that CIITA, the molecular switch of antigen presentation, plays a novel, unexpected function in skeletal homeostasis, independent of MHC Class II expression and T cells, by exerting a selective and intrinsic control of osteoclast differentiation and bone resorption in vivo.
authors.affiliation: Division of Genetics and Cell Biology and BoNetwork, DiBiT, San Raffaele Scientific Institute, Milano, Italy; Università Vita-Salute San Raffaele, Milano, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Benasciutti
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mariani
authors.forename: Laura
authors.initials: L
authors.lastname: Oliva
authors.forename: Maria
authors.initials: M
authors.lastname: Scolari
authors.forename: Egon
authors.initials: E
authors.lastname: Perilli
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Barras
authors.forename: Enrico
authors.initials: E
authors.lastname: Milan
authors.forename: Ugo
authors.initials: U
authors.lastname: Orfanelli
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Fazzalari
authors.forename: Lara
authors.initials: L
authors.lastname: Campana
authors.forename: Annalisa
authors.initials: A
authors.lastname: Capobianco
authors.forename: Luc
authors.initials: L
authors.lastname: Otten
authors.forename: Francesca
authors.initials: F
authors.lastname: Particelli
authors.forename: Hans
authors.initials: H
authors.lastname: Acha-Orbea
authors.forename: Fabio
authors.initials: F
authors.lastname: Baruffaldi
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio
authors.forename: Roberto
authors.initials: R
authors.lastname: Sitia
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
authors.forename: Simone
authors.initials: S
authors.lastname: Cenci
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: ADAPTIVE IMMUNITY; BONE; CIITA; MHC CLASS II; OSTEOCLAST DIFFERENTIATION