IL21R expressing CD14+CD16+ monocytes expand in multiple myeloma patients leading to increased osteoclasts

Bone marrow monocytes are primarily committed to osteoclast formation. It is, however, unknown whether potential primary alterations are specifically present in bone marrow monocytes of multiple myeloma patients, smoldering myeloma or monoclonal gammopathy of uncertain significance. Herein, 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. A higher number of bone marrow CD14+CD16+ cells was found in patients with active myeloma as compared to those with smoldering myeloma and monoclonal gammopathy of uncertain 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 multiple myeloma (but neither monoclonal gammopathy of uncertain significance nor smoldering myeloma) CD14+ cells significantly upregulated genes involved in osteoclast formation, including IL21R. IL21R mRNA over-expression by bone marrow CD14+ cells was independent from the presence of IL-21. Consistently, IL-21 production by T cells as well as IL-21 bone marrow levels were not significantly different among monoclonal gammopathies. Thereafter, we showed that IL21R over-expression in CD14+ cells increased osteoclast formation. Consistently, IL-21R signaling inhibition by Janex 1 suppressed osteoclast differentiation from bone marrow CD14+ cells of myeloma patients. Our results indicated that multiple myeloma patients showed distinct bone marrow monocyte features compared to those with indolent monoclonal gammopathies, supporting the role of IL21R over-expression by bone marrow CD14+ cells in enhanced osteoclast formation.