Macrophage inflammatory protein-1α is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor κB ligand

A complementary DNA expression library derived from marrow samples from myeloma patients was recently screened and human macrophage inflammatory protein-1 alpha (hMIP-1 alpha) was identified as an osteoclastogenic factor expressed in these samples. hMIP-1 alpha enhanced osteoclast (OCL) formation in human marrow cultures and by highly purified OCL precursors in a dose-dependent manner (5-200 pg/mL), Furthermore, hMIP-1 alpha enhanced OCL formation induced by human interleukin-6 (IL-6), which is produced by marrow stromal cells when they interact with myeloma cells. hMIP-1 alpha also enhanced OCL formation induced by parathyroid hormone-related protein (PTHrP) and receptor activator of nuclear factor KB ligand (RANKL), factors also implicated in myeloma bone disease. Time-course studies revealed that the hMIP-1 alpha acted during the last 2 weeks of the 3-week culture period. Reverse transcription-polymerase chain reaction analysis showed that the chemokine receptors for hMIP-1 alpha (CCR1 and CCR5) were expressed by human bone marrow and highly purified early OCL precursors. Furthermore, hMIP-1 alpha did not increase expression of RANKL, These data demonstrate that hMIP-1 alpha is an osteoclastogenic factor that appears to act directly on human OCL progenitors and acts at the later stages of OCL differentiation. These data further suggest that in patients with myeloma, MIP-la produced by myeloma cells, in combination with RANKL and IL-6 that are produced by marrow; stromal cells in response to myeloma cells, enhances OCL formation through their combined effects on Od precursors. (Blood. 2001; 97:3349-3353).