IL21R expressing CD14+CD16+ monocytes expand in multiple myeloma patients leading to increased osteoclasts
Marina Bolzoni,
Domenica Ronchetti,
Paola Storti,
Gaetano Donofrio,
Valentina Marchica,
Federica Costa,
Luca Agnelli,
Denise Toscani,
Rosanna Vescovini,
Katia Todoerti,
Sabrina Bonomini,
Gabriella Sammarelli,
Andrea Vecchi,
Daniela Guasco,
Fabrizio Accardi,
Benedetta Dalla Palma,
Barbara Gamberi,
Carlo Ferrari,
Antonino Neri,
Franco Aversa,
Nicola Giuliani
Affiliations
Marina Bolzoni
Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy
Domenica Ronchetti
Dept. of Oncology and Hemato-Oncology, University of Milan, Italy;Hematology Unit, “Fondazione IRCCS Ca’ Granda”, Ospedale Maggiore Policlinico, Milan, Italy
Paola Storti
Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy;CoreLab, University Hospital of Parma
Gaetano Donofrio
Dept. of Medical-Veterinary Science, University of Parma
Valentina Marchica
Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy;CoreLab, University Hospital of Parma
Federica Costa
Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy
Luca Agnelli
Dept. of Oncology and Hemato-Oncology, University of Milan, Italy;Hematology Unit, “Fondazione IRCCS Ca’ Granda”, Ospedale Maggiore Policlinico, Milan, Italy
Denise Toscani
Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy
Rosanna Vescovini
Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy
Katia Todoerti
Laboratory of Pre-clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy
Sabrina Bonomini
Hematology and BMT Center, University Hospital of Parma, Italy
Gabriella Sammarelli
Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy;Hematology and BMT Center, University Hospital of Parma, Italy
Andrea Vecchi
Infectious Disease Unit, University Hospital of Parma, Italy
Daniela Guasco
Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy
Fabrizio Accardi
Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy;Hematology and BMT Center, University Hospital of Parma, Italy
Benedetta Dalla Palma
Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy;Hematology and BMT Center, University Hospital of Parma, Italy
Barbara Gamberi
“Dip. Oncologico e Tecnologie Avanzate”, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
Carlo Ferrari
Infectious Disease Unit, University Hospital of Parma, Italy
Antonino Neri
Dept. of Oncology and Hemato-Oncology, University of Milan, Italy;Hematology Unit, “Fondazione IRCCS Ca’ Granda”, Ospedale Maggiore Policlinico, Milan, Italy
Franco Aversa
Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy;CoreLab, University Hospital of Parma;Hematology and BMT Center, University Hospital of Parma, Italy
Nicola Giuliani
Myeloma Unit, Dept. of Medicine and Surgery, University of Parma, Italy;CoreLab, University Hospital of Parma;Hematology and BMT Center, University Hospital of Parma, Italy
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 cultures ex vivo. Moreover, 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, including IL21R. IL21R mRNA 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 that IL21R over-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 of IL21R over-expression by bone marrow CD14+ cells in enhanced osteoclast formation.
