Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Semin Hematol. 2012 Jul;49(3):243-8. doi: 10.1053/j.seminhematol.2012.04.011.
Bone disease in patients with multiple myeloma (MM) is characterized by increase in the numbers and activity of bone-resorpting osteoclasts and decrease in the number and function of bone-formation osteoblasts. MM-triggered inhibition of bone formation may stem from suppression of Wnt/β-catenin signaling, a pivotal pathway in the differentiation of mesenchymal stem cells (MSC) into osteoblasts, and regulating production of receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) axis by osteoblasts. Proteasome inhibitors (PIs), such as bortezomib (Bz), induce activation of Wnt/β-catenin pathway and MSC differentiation toward osteoblasts. PIs also suppress osteoclastogenesis, possibly through regulating multiple pathways including NF-κB, Bim, and the ratio of RANKL/OPG. The critical role of PI in increasing osteoblast function and suppression of osteoclast activity is highlighted by clinical evidence of increases in bone formation and decreases in bone resorption makers. This review will discuss the function of PIs in stimulating bone formation and suppression of bone resorption, and the mechanism underlying this process that leads to inhibition bone disease in MM patients.
多发性骨髓瘤（MM）患者的骨骼疾病的特征是破骨细胞数量和活性增加，成骨细胞数量和功能减少。MM 触发的成骨抑制可能源于对 Wnt/β-catenin 信号通路的抑制，该通路是间充质干细胞（MSC）向成骨细胞分化的关键途径，并调节成骨细胞产生核因子-κB 配体（RANKL）/骨保护素（OPG）轴。蛋白酶体抑制剂（PIs），如硼替佐米（Bz），诱导 Wnt/β-catenin 通路激活和 MSC 向成骨细胞分化。PIs 还抑制破骨细胞生成，可能通过调节多个途径，包括 NF-κB、Bim 和 RANKL/OPG 的比值。PI 在增加成骨细胞功能和抑制破骨细胞活性方面的关键作用，通过增加骨形成标志物和减少骨吸收标志物得到了临床证据的证实。这篇综述将讨论 PIs 在刺激骨形成和抑制骨吸收方面的作用，以及导致 MM 患者骨骼疾病抑制的这一过程的潜在机制。
