Macrophage inflammatory protein-1 alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappa B ligand

A complementary DNA expression library derived from marrow samples from mye loma patients was recently screened and human macrophage inflammatory prote in-1 alpha (hMIP-1 alpha) was identified as an osteoclastogenic factor expr essed in these samples. hMIP-1 alpha enhanced osteoclast (OCL) formation in human marrow cultures and by highly purified OCL precursors in a dose-depe ndent manner (5-200 pg/mL), Furthermore, hMIP-1 alpha enhanced OCL formatio n induced by human interleukin-6 (IL-6), which is produced by marrow stroma l cells when they interact with myeloma cells. hMIP-1 alpha also enhanced O CL formation induced by parathyroid hormone-related protein (PTHrP) and rec eptor activator of nuclear factor KB ligand (RANKL), factors also implicate d in myeloma bone disease. Time-course studies revealed that the hMIP-1 alp ha acted during the last 2 weeks of the 3-week culture period. Reverse tran scription-polymerase chain reaction analysis showed that the chemokine rece ptors 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 progen itors and acts at the later stages of OCL differentiation. These data furth er 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 ce lls in response to myeloma cells, enhances OCL formation through their comb ined effects on Od precursors. (Blood. 2001; 97:3349-3353).