Immunomodulatory drugs lenalidomide and pomalidomide inhibit multiple Myeloma-induced osteoclast formation and the RANKL/OPG ratio in the myeloma microenvironment targeting the expression of adhesion molecules
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Published:25th Mar 2020
Source: Experimental Hematology
Multiple myeloma (MM)-induced osteoclast (OC) formation is mainly due to an imbalance of the receptor activator of NF-kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio in favor of RANKL in the bone microenvironment and to the CCL3 production by MM cells. The purpose of the study was to investigate the effect of the immunomodulatory drugs on RANKL/OPG ratio, the production of pro-osteoclatogenic cytokines and MM-induced OC formation. We found that in vivo concentrations of both Lenalidomide (LEN) and Pomalidomide (POM), significantly blunted RANKL up-regulation normalizing the RANKL/OPG ratio in human osteoprogenitor cells (PreOBs) when co-cultured with MM cells and also inhibited CCL3 production by MM cells. A reduction in CD49d expression, a molecule critically involved in RANKL up-regulation in the MM microenvironment, accompanied this effect. Consistently, the pro-osteoclastogenic property of MM cells co-cultured with PreOBs was reduced by both LEN and POM. We further investigated the effect of these drugs on the transcriptional profile of both MM cells and PreOBs by microarray analysis, which showed that adhesion molecule such as ITGA8, and ICAM2 are significantly down-regulated in MM cells. Our data suggests that LEN and POM inhibits MM-induced OC formation through normalization of the RANKL/OPG ratio targeting the expression of adhesion molecules by MM cells.