title: IL21Rexpressing CD14+CD16+monocytes expand in multiple myeloma patients leading to increased osteoclasts.
abstract: Bone marrow monocytes are primarily committed to osteoclast formation. It is, however, unknown whether potential primary alterations are specifically present in bone marrow monocytes from patients with multiple myeloma, smoldering myeloma or monoclonal gammopathy of undetermined significance. We analyzed the immunophenotypic and transcriptional profiles of bone marrow CD14+monocytes in a cohort of patients with different types of monoclonal gammopathies to identify alterations involved in myeloma-enhanced osteoclastogenesis. The number of bone marrow CD14+CD16+cells was higher in patients with active myeloma than in those with smoldering myeloma or monoclonal gammopathy of undetermined significance. Interestingly, sorted bone marrow CD14+CD16+cells from myeloma patients were more pro-osteoclastogenic than CD14+CD16-cells in culturesex vivoMoreover, transcriptional analysis demonstrated that bone marrow CD14+cells from patients with multiple myeloma (but neither monoclonal gammopathy of undetermined significance nor smoldering myeloma) significantly upregulated genes involved in osteoclast formation, includingIL21RIL21RmRNA over-expression by bone marrow CD14+cells was independent of the presence of interleukin-21. Consistently, interleukin-21 production by T cells as well as levels of interleukin-21 in the bone marrow were not significantly different among monoclonal gammopathies. Thereafter, we showed thatIL21Rover-expression in CD14+cells increased osteoclast formation. Consistently, interleukin-21 receptor signaling inhibition by Janex 1 suppressed osteoclast differentiation from bone marrow CD14+cells of myeloma patients. Our results indicate that bone marrow monocytes from multiple myeloma patients show distinct features compared to those from patients with indolent monoclonal gammopathies, supporting the role ofIL21Rover-expression by bone marrow CD14+cells in enhanced osteoclast formation.
authors.affiliation: Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Bolzoni
authors.affiliation: Dept. of Oncology and Hemato-Oncology, University of Milan, Italy.|Hematology Unit, "Fondazione IRCCS Ca' Granda", Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Ronchetti
authors.affiliation: Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy.|CoreLab, University Hospital of Parma, Rionero in Vulture, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Storti
authors.affiliation: Dept. of Medical-Veterinary Science, University of Parma, Rionero in Vulture, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Donofrio
authors.affiliation: Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy.|CoreLab, University Hospital of Parma, Rionero in Vulture, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Marchica
authors.affiliation: Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Costa
authors.affiliation: Dept. of Oncology and Hemato-Oncology, University of Milan, Italy.|Hematology Unit, "Fondazione IRCCS Ca' Granda", Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Agnelli
authors.affiliation: Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy.
authors.forename: Denise
authors.initials: D
authors.lastname: Toscani
authors.affiliation: Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Vescovini
authors.affiliation: Laboratory of Pre-clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Todoerti
authors.affiliation: Hematology and BMT Center, University Hospital of Parma, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bonomini
authors.affiliation: Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy.|Hematology and BMT Center, University Hospital of Parma, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sammarelli
authors.affiliation: Infectious Disease Unit, University Hospital of Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vecchi
authors.affiliation: Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Guasco
authors.affiliation: Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy.|Hematology and BMT Center, University Hospital of Parma, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Accardi
authors.affiliation: Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy.|Hematology and BMT Center, University Hospital of Parma, Italy.
authors.forename: Benedetta Dalla
authors.initials: BD
authors.lastname: Palma
authors.affiliation: "Dip. Oncologico e Tecnologie Avanzate", IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gamberi
authors.affiliation: Infectious Disease Unit, University Hospital of Parma, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferrari
authors.affiliation: Dept. of Oncology and Hemato-Oncology, University of Milan, Italy.|Hematology Unit, "Fondazione IRCCS Ca' Granda", Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.affiliation: Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy.|CoreLab, University Hospital of Parma, Rionero in Vulture, Italy.|Hematology and BMT Center, University Hospital of Parma, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Aversa
authors.affiliation: Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy nicola.giuliani@unipr.it.|CoreLab, University Hospital of Parma, Rionero in Vulture, Italy.|Hematology and BMT Center, University Hospital of Parma, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Giuliani
mesh_terms: D015415:Biomarkers; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D016000:Cluster Analysis; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010010:Osteoclasts / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D053655:Receptors, Interleukin-21 / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D012333:RNA, Messenger; D017452:Receptors, IgG; D053655:Receptors, Interleukin-21