Gkikopoulou Evi, Syrigos Christos-Chrysovalantis, Mantogiannakou Ioanna, Petraki Chrysa-Eleni, Stathopoulou Melina, Dragolia Melina, Rinotas Vagelis, Ntafis Vasileios, Rauner Martina, Douni Eleni
Institute for Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming", Fleming 34, 16672 Vari, Greece.
Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Iera Odos 75, 11855 Athens, Greece.
Int J Mol Sci. 2025 May 22;26(11):4990. doi: 10.3390/ijms26114990.
Receptor activator of nuclear factor-κB ligand (RANKL) is essential for osteoclast formation and bone resorption, in osteolytic conditions such as osteoporosis and bone metastases. However, its role in metastasis progression remains incompletely understood. Herein, we examined whether the overexpression of human RANKL in transgenic mice (TgRANKL) affects their susceptibility to breast cancer bone metastasis compared to their wild-type (WT) littermates. Bone metastasis was induced by injecting EO771 mouse mammary adenocarcinoma cells into the caudal artery of syngeneic WT and TgRANKL mice. RANKL overexpression led to an earlier onset and increased burden of bone metastasis in EO771-bearing TgRANKL mice compared to WT mice. It also exacerbated the bone destruction caused by metastasis-associated osteolysis. The prophylactic inhibition of RANKL activity with denosumab, a monoclonal antibody targeting human RANKL, prevented osteolysis and significantly reduced the incidence and progression of bone metastases in TgRANKL mice. However, the therapeutic denosumab treatment had no effect on metastasis incidence or tumor burden, although it alleviated osteolysis. The treatment with zoledronic acid, an anti-resorptive agent inhibiting osteoclast activity, yielded results similar to those of denosumab. These findings emphasize the significance of initiating early treatment with anti-resorptive agents such as denosumab or zoledronic acid to reduce the risk of bone metastasis in patients at high risk.
核因子κB受体激活剂配体（RANKL）在破骨细胞形成和骨吸收过程中起着至关重要的作用，在诸如骨质疏松症和骨转移等溶骨性疾病中亦是如此。然而，其在转移进展中的作用仍未完全明确。在此，我们研究了与野生型（WT）同窝小鼠相比，转基因小鼠（TgRANKL）中人类RANKL的过表达是否会影响它们对乳腺癌骨转移的易感性。通过将EO771小鼠乳腺腺癌细胞注射到同基因WT和TgRANKL小鼠的尾动脉中诱导骨转移。与WT小鼠相比，RANKL过表达导致携带EO771的TgRANKL小鼠骨转移发病更早且负担加重。它还加剧了转移相关骨溶解所导致的骨质破坏。使用地诺单抗（一种靶向人类RANKL的单克隆抗体）预防性抑制RANKL活性可预防骨溶解，并显著降低TgRANKL小鼠骨转移的发生率和进展。然而，尽管地诺单抗治疗缓解了骨溶解，但对转移发生率或肿瘤负担并无影响。使用唑来膦酸（一种抑制破骨细胞活性的抗吸收剂）进行治疗得到了与地诺单抗相似的结果。这些发现强调了尽早使用地诺单抗或唑来膦酸等抗吸收剂进行治疗以降低高危患者骨转移风险的重要性。
