Hematology and BMT Center, University of Parma, Parma, Italy.
Exp Hematol. 2013 Apr;41(4):387-97.e1. doi: 10.1016/j.exphem.2012.11.005. Epub 2012 Nov 23.
Multiple myeloma (MM)-induced osteoclast (OC) formation is mainly due to an imbalance of the receptor activator NF-κB 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-osteoclastogenic cytokines, and MM-induced OC formation. We found that in vivo concentrations of both lenalidomide (LEN) and pomalidomide (POM) significantly blunted RANKL upregulation 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 upregulation 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 molecules, such as ITGA8 and ICAM2, are significantly downregulated in MM cells. Our data suggest that LEN and POM inhibit MM-induced OC formation through normalization of the RANKL/OPG ratio targeting the expression of adhesion molecules by MM cells.
多发性骨髓瘤（MM）诱导的破骨细胞（OC）形成主要是由于骨微环境中 RANKL-骨保护素（OPG）比率失衡，有利于 RANKL，以及 MM 细胞产生 CCL3。本研究旨在探讨免疫调节剂对 RANKL/OPG 比率、促破骨细胞生成细胞因子的产生以及 MM 诱导的 OC 形成的影响。我们发现，体内浓度的来那度胺（LEN）和泊马度胺（POM）在与 MM 细胞共培养时，显著抑制 RANKL 的上调，使人类成骨前体细胞（PreOBs）中的 RANKL/OPG 比率正常化，同时也抑制 MM 细胞产生 CCL3。这种作用伴随着 CD49d 表达的减少，CD49d 是 MM 微环境中 RANKL 上调的关键分子。一致地，与 PreOB 共培养的 MM 细胞的促破骨细胞生成特性被 LEN 和 POM 降低。我们进一步通过微阵列分析研究了这些药物对 MM 细胞和 PreOBs 转录谱的影响，结果表明粘附分子，如 ITGA8 和 ICAM2，在 MM 细胞中显著下调。我们的数据表明，LEN 和 POM 通过靶向 MM 细胞表达粘附分子来抑制 MM 诱导的 OC 形成，使 RANKL/OPG 比率正常化。
