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CC-Chemokine Ligand 20/Macrophage Inflammatory Protein-3 and CC-Chemokine Receptor 6 Are Overexpressed in Myeloma Microenvironment Related to Osteolytic Bone Lesions

¹ Hematology and Bone Marrow Transplantation Center, ² "Dipartimento Di Genetica," and ³ Department of Pathology, University of Parma, Parma, Italy and ⁴ Laboratory of Immunology and Genetics, I.O.R., Bologna, Italy

Requests for reprints: Nicola Giuliani, Hematology and Bone Marrow Transplantation Center, Department of Internal Medicine and Biomedical Science, University of Parma, via Gramsci 14, 43100 Parma, Italy. Phone: 39-0521-903299; Fax: 39-0521-903264; E-mail: Nicola.Giuliani{at}unipr.it or N_giuliani{at}yahoo.com.

Key Words: Multiple Myeloma • Microenvironment • Chemokines • Osteoclasts • Osteoblasts

The expression of the chemokine CC-chemokine ligand 20 (CCL20)/macrophage inflammatory protein (MIP)-3 and its receptor CC-chemokine receptor 6 (CCR6) by multiple myeloma (MM) and microenvironment cells and their potential relationship with osteoclast (OC) formation and osteolytic bone lesions in MM patients was investigated in this study. First, we found that MM cells rarely produce CCL20/MIP-3 but up-regulate its production by bone marrow (BM) osteoprogenitor cells and osteoblasts in coculture with the involvement of soluble factors as interleukin-1β and tumor necrosis factor . MM cells also stimulate both CCL20/MIP-3 and CCR6 expression by OCs in coculture. Thereafter, we showed that CCL20/MIP-3 significantly increases both the number of multinucleated tartrate-resistant acid phosphatase–positive OCs and receptor activator of nuclear factor-B–positive OC progenitor cells similar to CCL3/MIP-1. Finally, we found that blocking anti-CCL20/MIP-3 and anti-CCR6 antibodies significantly inhibits MM-induced OC formation. In vitro data were further expanded in vivo analyzing a total number of 64 MM patients. Significantly higher CCL20/MIP-3 levels were detected in MM patients versus monoclonal gammopathy of uncertain significance (MGUS) subjects and in MM osteolytic patients versus nonosteolytic ones. Moreover, a significant increase of CCL20/MIP-3–positive osteoblasts in osteolytic MM patients compared with nonosteolytic ones was observed. Interestingly, no significant difference in BM CCL20/MIP-3 expression and level was observed between MGUS and nonosteolytic MM patients. Our data indicate that CCL20/MIP-3 and its receptor CCR6 are up-regulated in the bone microenvironment by MM cells and contribute to OC formation and osteolytic bone lesions in MM patients. [Cancer Res 2008;68(16):6840–50]