Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma

Abstract

Abstract This study was designed to determine if macrophage inhibitory protein-1 (MIP-1), a recently described osteoclast (OCL) stimulatory factor,1 was present in marrow from patients with multiple myeloma (MM) and possibly involved in the bone destructive process. MIP-1, but not interleukin-1β (IL-1β), tumor necrosis factor-β (TNF-β), or interleukin-6 (IL-6), messenger RNA was elevated in freshly isolated bone marrow from 3 of 4 patients with MM compared to normal controls. Furthermore, enzyme-linked immunosorbent assays of freshly isolated bone marrow plasma detected increased concentrations of hMIP-1 (range, 75-7784 pg/mL) in 8 of 13 patients (62%) with active myeloma, in 3 of 18 patients (17%) with stable myeloma (range, 75-190.3), as well as in conditioned media from 4 of 5 lymphoblastoid cell lines (LCLs) derived from patients with MM. Mildly elevated levels of MIP-1 were detected in 3 of 14 patients (21%) with other hematologic diagnoses (range, 80.2-118.3, median value of 96 pg/mL) but not in normal controls (0 of 7). MIP-1 was not detected in the peripheral blood of any patients with MM. In addition, recombinant hMIP-1 induced OCL formation in human bone marrow cultures. Importantly, addition of a neutralizing antibody to MIP-1 to human bone marrow cultures treated with freshly isolated marrow plasma from patients with MM blocked the increased OCL formation induced by these marrow samples but had no effect on control levels of OCL formation. Thus, high levels of MIP-1 are expressed in marrow samples from patients with MM, but not in marrow from patients with other hematologic disorders or controls, and support an important role for MIP-1 as one of the major factors responsible for the increased OCL stimulatory activity in patients with active MM.