Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, 70124, Bari, Italy.
Adv Exp Med Biol. 2011;714:113-28. doi: 10.1007/978-94-007-0782-5_5.
Multiple myeloma (MM) is a hematologic malignancy whose progression may account for uncontrolled osteoclastogenesis promoted by the malignant plasma cells within the marrow microenvironment. Osteoclasts are multinucleated cells derived from the fusion of myeloid progenitors such as monocytes/macrophages, in response to specific differentiation factors released within the marrow niche, that are significantly deregulated in MM. In this malignancy DC-STAMP, a major fusogen protein enrolled by pre-osteoclasts, is highly expressed by peripheral macrophages, whereas dendritic cells and myeloma plasma cells show high fusogenic susceptibility and under specific conditions transdifferentiate to osteoclasts. In particular, the malignant plasma cells, besides altered ploidy, expression of cancer stem cell phenotype and high metastasizing capability, are able to express phenotypic markers of osteclasts, namely the proteolytic enzymes for the bone matrix, and to activate the β3 transcriptional pathway leading to ERK1/2 phosphorylation and initiation of the bone resorbing activity. Thus, based on the imbalanced osteoclast formation and activity that involve cells constitutively uncommitted to osteoclast differentiation, both homotypic and heterotypic cell fusions in myeloma marrow microenvironment represent a major pathogenetic event that drives the development and progression of the skeleton devastation typical of the myeloma bone disease.
多发性骨髓瘤（MM）是一种血液恶性肿瘤，其进展可能导致骨髓微环境中恶性浆细胞引起的破骨细胞生成失控。破骨细胞是由单核细胞/巨噬细胞等髓系祖细胞融合而成的多核细胞，对骨髓龛内释放的特定分化因子有反应，在 MM 中显著失调。在这种恶性肿瘤中，DC-STAMP 是一种主要的融合蛋白，被前破骨细胞募集，在外周巨噬细胞中高度表达，而树突状细胞和骨髓瘤浆细胞表现出高融合易感性，并在特定条件下向破骨细胞转分化。特别是恶性浆细胞，除了改变倍性、表达癌症干细胞表型和高转移能力外，还能够表达破骨细胞的表型标志物，即骨基质的蛋白水解酶，并激活β3 转录途径，导致 ERK1/2 磷酸化和启动骨吸收活性。因此，基于涉及持续不受破骨细胞分化影响的细胞的不平衡破骨细胞形成和活性，骨髓瘤骨髓微环境中的同型和异型细胞融合代表了驱动典型骨髓瘤骨病骨骼破坏发展和进展的主要发病事件。
