Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease.
Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease.
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DOI：
10.1016/j.bone.2016.07.007
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发表时间：
2016-10
期刊：
影响因子：
4.1
通讯作者：
Sterling JA
中科院分区：
文献类型：
--
作者：
Nyman JS;Merkel AR;Uppuganti S;Nayak B;Rowland B;Makowski AJ;Oyajobi BO;Sterling JA
多发性骨髓瘤（MM）患者经常发生肿瘤引起的骨破坏，但没有治疗完全消除肿瘤或完全逆转骨丢失。转化生长因子-β（TGF-β）活性通常导致肿瘤诱导的骨病，临床前研究表明，TGF-β抑制可改善骨体积并减少骨转移性乳腺癌的肿瘤生长。我们假设抑制TGF-β信号传导也能减少MM荷瘤小鼠的肿瘤生长，增加骨体积，并改善椎体强度。在接种小鼠5 TGM 1 MM细胞后，我们用TGF-β抑制性（1D 11）或对照（13 C4）抗体治疗骨髓瘤荷瘤（免疫活性KaLwRij和免疫功能低下的Rag 2 −/−）小鼠4周，同时使用或不使用抗骨髓瘤药物硼替佐米。TGF-β抑制增加了骨小梁体积，改善了骨小梁结构，增加了骨小梁的组织矿物质密度（通过离体显微计算机断层扫描评估），并与生物力学压缩试验中显著更大的椎体强度相关。血清单克隆副蛋白滴度和脾脏重量显示，1D 11单药治疗未降低总体MM肿瘤负荷。1D 11和硼替佐米的联合治疗增加了椎体强度，降低了肿瘤负荷，减少了股骨干骺端的皮质病变，尽管在股骨中段的三点弯曲试验中没有显著改善皮质骨强度。总体而言，我们的数据为评价TGF-β信号传导抑制与现有抗骨髓瘤药物联合作为改善骨髓瘤骨病患者结局的潜在治疗策略提供了依据。
Multiplemyeloma (MM) patients frequently develop tumor-induced bone destruction, yet no therapy completely eliminates the tumor or fully reverses bone loss. Transforming growth factor-β (TGF-β) activity often contributes to tumor-induced bone disease, and pre-clinical studies have indicated that TGF-β inhibition improves bone volume and reduces tumor growth in bone metastatic breast cancer. We hypothesized that inhibition of TGF-β signaling also reduces tumor growth, increases bone volume, and improves vertebral body strength in MM-bearing mice. We treated myeloma tumor-bearing (immunocompetent KaLwRij and immunocompromised Rag2 −/−) mice with a TGF-β inhibitory (1D11) or control (13C4) antibody, with or without the anti-myeloma drug bortezomib, for 4 weeks after inoculation of murine 5TGM1 MM cells. TGF-β inhibition increased trabecular bone volume, improved trabecular architecture, increased tissue mineral density of the trabeculae as assessed by ex vivo micro-computed tomography, and was associated with significantly greater vertebral body strength in biomechanical compression tests. Serum monoclonal paraprotein titers and spleen weights showed that 1D11 monotherapy did not reduce overall MM tumor burden. Combination therapy with 1D11 and bortezomib increased vertebral body strength, reduced tumor burden, and reduced cortical lesions in the femoral metaphysis, although it did not significantly improve cortical bone strength in three-point bending tests of the mid-shaft femur. Overall, our data provides rationale for evaluating inhibition of TGF-β signaling in combination with existing anti-myeloma agents as a potential therapeutic strategy to improve outcomes in patients with myeloma bone disease.