Breitkreutz Iris, Raab Marc S, Vallet Sonia, Hideshima Teru, Raje Noopur, Chauhan Dharminder, Munshi Nikhil C, Richardson Paul G, Anderson Kenneth C
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Br J Haematol. 2007 Oct;139(1):55-63. doi: 10.1111/j.1365-2141.2007.06747.x.
Osteolytic bone disease in multiple myeloma (MM) is associated with upregulation of osteoclast (OCL) activity and constitutive inhibition of osteoblast function. The extracellular signal-regulated kinase 1/2 (ERK1/2) pathway mediates OCL differentiation and maturation. We hypothesized that inhibition of ERK1/2 could prevent OCL differentiation and downregulate OCL function. It was found that AZD6244, a mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, blocked OCL differentiation and formation in a dose-dependent manner, evidenced by decreased alphaVbeta3-integrin expression and tartrate-resistant acid phosphatase positive (TRAP+) cells. Functional dentine disc cultures showed inhibition of OCL-induced bone resorption by AZD6244. Major MM growth and survival factors produced by OCLs including B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL), as well as macrophage inflammatory protein (MIP-1alpha), which mediates OCL differentiation and MM, were also significantly inhibited by AZD6244. In addition to ERK inhibition, NFATc1 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1) and c-fos were both downregulated, suggesting that AZD6244 targets a later stage of OCL differentiation. These results indicate that AZD6244 inhibits OCL differentiation, formation and bone resorption, thereby abrogating paracrine MM cell survival in the bone marrow microenvironment. The present study therefore provides a preclinical rationale for the evaluation of AZD6244 as a potential new therapy for patients with MM.
多发性骨髓瘤（MM）中的溶骨性骨病与破骨细胞（OCL）活性上调和成骨细胞功能的持续性抑制相关。细胞外信号调节激酶1/2（ERK1/2）通路介导OCL的分化和成熟。我们推测抑制ERK1/2可阻止OCL分化并下调OCL功能。研究发现，丝裂原活化或细胞外信号调节蛋白激酶（MEK）抑制剂AZD6244以剂量依赖方式阻断OCL分化和形成，αVβ3整合素表达降低和抗酒石酸酸性磷酸酶阳性（TRAP+）细胞减少证明了这一点。功能性牙本质盘培养显示AZD6244抑制OCL诱导的骨吸收。OCL产生的主要MM生长和存活因子，包括B细胞活化因子（BAFF）和增殖诱导配体（APRIL），以及介导OCL分化和MM的巨噬细胞炎性蛋白（MIP-1α），也被AZD6244显著抑制。除抑制ERK外，活化T细胞核因子（细胞质，钙调神经磷酸酶依赖性1）NFATc1和c-fos均下调，表明AZD6244靶向OCL分化的后期阶段。这些结果表明AZD6244抑制OCL分化、形成和骨吸收，从而消除骨髓微环境中旁分泌的MM细胞存活。因此，本研究为评估AZD6244作为MM患者潜在新疗法提供了临床前理论依据。
