1] Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan [2] Department of Biomaterials and Bioengineering, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan [3] Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Department of Histology and Oral Histology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Leukemia. 2015 Jan;29(1):207-17. doi: 10.1038/leu.2014.147. Epub 2014 May 2.
Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-α, transforming growth factor-β (TGF-β) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF-β signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction.
Pim-2 激酶在多发性骨髓瘤 (MM) 细胞中过表达，以增强其生长和存活，被认为是 MM 的一种新的治疗靶点。然而，Pim-2 抑制对 MM 中的骨病的影响尚不清楚。我们在这里证明，在存在已知的 MM 成骨细胞抑制剂的情况下，包括白细胞介素-3 (IL-3)、IL-7、肿瘤坏死因子-α、转化生长因子-β (TGF-β) 和激活素 A 以及 MM 细胞条件培养基中，骨髓基质细胞和 MC3T3-E1 前成骨细胞中 Pim-2 的表达也上调。BMP-2 的体外成骨作用被 Pim-2 的强制表达所阻断，这表明 Pim-2 是成骨作用的负调节剂。用 Pim-2 短发夹 RNA 以及 Pim 抑制剂 SMI-16a 处理可成功恢复所有上述抑制因子和 MM 细胞抑制的成骨作用。SMI-16a 处理增强了 BMP-2 介导的合成代谢信号，同时抑制了 TGF-β 信号。此外，用新合成的噻唑烷-2,4-二酮同系物 12a-OH 以及其原型 SMI-16a 治疗可有效预防骨破坏，同时抑制 MM 动物模型中的 MM 肿瘤生长。因此，Pim-2 在 MM 中的肿瘤进展和骨丢失中可能具有关键作用，Pim-2 抑制可能成为靶向 MM 细胞-骨髓相互作用的重要治疗策略。
