Division of Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
PLoS One. 2010 Dec 30;5(12):e15755. doi: 10.1371/journal.pone.0015755.
The ARF tumor suppressor regulates p53 as well as basic developmental processes independent of p53, including osteoclast activation, by controlling ribosomal biogenesis. Here we provide evidence that ARF is a master regulator of bone remodeling and osteosarcoma (OS) development in mice. Arf(-/-) mice displayed increased osteoblast (OB) and osteoclast (OC) activity with a significant net increase in trabecular bone volume. The long bones of Arf(-/-) mice had increased expression of OB genes while Arf(-/-) OB showed enhanced differentiation in vitro. Mice transgenic for the Tax oncogene develop lymphocytic tumors with associated osteolytic lesions, while Tax+Arf(-/-) mice uniformly developed spontaneous OS by 7 months of age. Tax+Arf(-/-) tumors were well differentiated OS characterized by an abundance of new bone with OC recruitment, expressed OB markers and displayed intact levels of p53 mRNA and reduced Rb transcript levels. Cell lines established from OS recapitulated characteristics of the primary tumor, including the expression of mature OB markers and ability to form mineralized tumors when transplanted. Loss of heterozygosity in OS tumors arising in Tax+Arf(+/-) mice emphasized the necessity of ARF-loss in OS development. Hypothesizing that inhibition of ARF-regulated bone remodeling would repress development of OS, we demonstrated that treatment of Tax+Arf(-/-) mice with zoledronic acid, a bisphosphonate inhibitor of OC activity and repressor of bone turnover, prevented or delayed the onset of OS. These data describe a novel role for ARF as a regulator of bone remodeling through effects on both OB and OC. Finally, these data underscore the potential of targeting bone remodeling as adjuvant therapy or in patients with genetic predispositions to prevent the development of OS.
ARF 肿瘤抑制因子通过控制核糖体生物发生来调节 p53 以及独立于 p53 的基本发育过程，包括破骨细胞激活。在这里，我们提供了证据表明 ARF 是小鼠骨重塑和骨肉瘤（OS）发展的主要调节因子。Arf(-/-) 小鼠表现出增加的成骨细胞（OB）和破骨细胞（OC）活性，小梁骨体积有显著的净增加。Arf(-/-) 小鼠的长骨中 OB 基因表达增加，而 Arf(-/-)OB 在体外显示出增强的分化。携带 Tax 癌基因的转基因小鼠会发展出淋巴细胞肿瘤，并伴有溶骨性病变，而 Tax+Arf(-/-) 小鼠在 7 个月大时会均匀地自发发展出 OS。Tax+Arf(-/-) 肿瘤是分化良好的 OS，其特征是大量新骨形成，伴有 OC 募集，表达 OB 标志物，并显示 p53 mRNA 水平完整和 Rb 转录本水平降低。从 OS 建立的细胞系再现了原发性肿瘤的特征，包括成熟 OB 标志物的表达和当移植时形成矿化肿瘤的能力。在 Tax+Arf(+/-) 小鼠中出现的 OS 肿瘤的杂合性丢失强调了 ARF 缺失在 OS 发展中的必要性。假设抑制 ARF 调节的骨重塑会抑制 OS 的发展，我们证明了用唑来膦酸治疗 Tax+Arf(-/-) 小鼠，唑来膦酸是一种抑制 OC 活性和抑制骨转换的双膦酸盐，可预防或延迟 OS 的发生。这些数据描述了 ARF 通过对 OB 和 OC 的影响作为骨重塑调节剂的新作用。最后，这些数据强调了靶向骨重塑作为辅助治疗或在具有遗传易感性的患者中预防 OS 发展的潜力。
