Department of Medicine, Hematology Oncology, Indiana University, Indianapolis, IN.
J Bone Miner Res. 2014 Jun;29(6):1456-65. doi: 10.1002/jbmr.2158.
Measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) and mutation of the SQSTM1 (p62) gene contribute to the increased OCL activity in Paget's disease (PD). OCLs expressing MVNP display many of the features of PD OCLs. Interleukin-6 (IL-6) production is essential for the pagetic phenotype, because transgenic mice with MVNP targeted to OCLs develop pagetic OCLs and lesions, but this phenotype is absent when MVNP mice are bred to IL-6(-/-) mice. In contrast, mutant p62 expression in OCL precursors promotes receptor activator of NF-κB ligand (RANKL) hyperresponsivity and increased OCL production, but OCLs that form have normal morphology, are not hyperresponsive to 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3 ), nor produce elevated levels of IL-6. We previously generated p62(P394L) knock-in mice (p62KI) and found that although OCL numbers were increased, the mice did not develop pagetic lesions. However, mice expressing both MVNP and p62KI developed more exuberant pagetic lesions than mice expressing MVNP alone. To examine the role of elevated IL-6 in PD and determine if MVNP mediates its effects primarily through elevation of IL-6, we generated transgenic mice that overexpress IL-6 driven by the tartrate-resistant acid phosphatase (TRAP) promoter (TIL-6 mice) and produce IL-6 at levels comparable to MVNP mice. These were crossed with p62KI mice to determine whether IL-6 overexpression cooperates with mutant p62 to produce pagetic lesions. OCL precursors from p62KI/TIL-6 mice formed greater numbers of OCLs than either p62KI or TIL-6 OCL precursors in response to 1,25-(OH)2 D3 . Histomorphometric analysis of bones from p62KI/TIL-6 mice revealed increased OCL numbers per bone surface area compared to wild-type (WT) mice. However, micro-quantitative CT (µQCT) analysis did not reveal significant differences between p62KI/TIL-6 and WT mice, and no pagetic OCLs or lesions were detected in vivo. Thus, increased IL-6 expression in OCLs from p62KI mice contributes to increased responsivity to 1,25-(OH)2 D3 and increased OCL numbers, but is not sufficient to induce Paget's-like OCLs or bone lesions in vivo.
破骨细胞（OCLs）中麻疹病毒核衣壳蛋白（MVNP）的表达和 SQSTM1（p62）基因的突变导致 Pagets 病（PD）中 OCL 活性增加。表达 MVNP 的 OCL 表现出许多 PD OCL 的特征。白细胞介素-6（IL-6）的产生对于 pagetic 表型是必不可少的，因为靶向 OCL 的 MVNP 转基因小鼠会发展成 pagetic OCL 和病变，但当 MVNP 小鼠与 IL-6（-/-）小鼠繁殖时，这种表型就不存在了。相比之下，OCL 前体中突变的 p62 表达促进了核因子-κB 配体（RANKL）的超反应性和 OCL 产量的增加，但形成的 OCL 具有正常的形态，对 1,25-二羟基维生素 D3（1,25-（OH）2 D3）没有过度反应，也不会产生升高水平的 IL-6。我们之前生成了 p62（P394L）基因敲入小鼠（p62KI），并发现尽管 OCL 数量增加，但小鼠并未发展成 pagetic 病变。然而，表达 MVNP 和 p62KI 的小鼠比单独表达 MVNP 的小鼠发展出更旺盛的 pagetic 病变。为了研究升高的 IL-6 在 PD 中的作用，并确定 MVNP 是否主要通过升高 IL-6 来发挥其作用，我们生成了转基因小鼠，其由抗酒石酸酸性磷酸酶（TRAP）启动子（TIL-6 小鼠）驱动的 IL-6 过表达，并产生与 MVNP 小鼠相当水平的 IL-6。这些与 p62KI 小鼠杂交，以确定 IL-6 过表达是否与突变的 p62 协同作用以产生 pagetic 病变。与野生型（WT）小鼠相比，p62KI/TIL-6 小鼠的 OCL 前体对 1,25-（OH）2 D3 的反应形成了更多数量的 OCL。p62KI/TIL-6 小鼠骨的组织形态计量学分析显示，与 WT 小鼠相比，每个骨表面区域的 OCL 数量增加。然而，微定量 CT（µQCT）分析并未显示 p62KI/TIL-6 和 WT 小鼠之间有显著差异，并且在体内未检测到 Pagets 样 OCL 或病变。因此，p62KI 小鼠的 OCL 中升高的 IL-6 表达导致对 1,25-（OH）2 D3 的反应性增加和 OCL 数量增加，但不足以在体内诱导 Pagets 样 OCL 或骨病变。
