Chemotherapy is important for cancer treatment, however, toxicities limit its use. While great strides have been made to ameliorate the acute toxicities induced by chemotherapy, long-term comorbidities including bone loss remain a significant problem. Chemotherapy-driven estrogen loss is postulated to drive bone loss, but significant data suggests the existence of an estrogen-independent mechanism of bone loss. Using clinically relevant mouse models, we showed that senescence and its senescence-associated secretory phenotype (SASP) contribute to chemotherapy-induced bone loss that can be rescued by depleting senescent cells. Chemotherapy-induced SASP could be limited by targeting the p38MAPK-MK2 pathway, which resulted in preservation of bone integrity in chemotherapy-treated mice. These results transform our understanding of chemotherapy-induced bone loss by identifying senescent cells as major drivers of bone loss and the p38MAPK-MK2 axis as a putative therapeutic target that can preserve bone and improve a cancer survivor's quality of life. SIGNIFICANCE: Senescence drives chemotherapy-induced bone loss that is rescued by p38MAPK or MK2 inhibitors. These findings may lead to treatments for therapy-induced bone loss, significantly increasing quality of life for cancer survivors.

中文翻译：

---

治疗诱导的衰老会导致骨质流失。

化疗对于癌症治疗很重要，然而，毒性限制了它的使用。虽然在改善化疗引起的急性毒性方面取得了很大进展，但包括骨质流失在内的长期合并症仍然是一个重大问题。化疗驱动的雌激素流失被认为会导致骨质流失，但重要数据表明存在一种不依赖雌激素的骨质流失机制。使用临床相关的小鼠模型，我们发现衰老及其衰老相关分泌表型 (SASP) 有助于化疗引起的骨丢失，可以通过耗尽衰老细胞来挽救。化疗诱导的 SASP 可以通过靶向 p38MAPK-MK2 通路来限制，这导致化疗治疗小鼠的骨骼完整性得到保护。这些结果通过将衰老细胞确定为骨质流失的主要驱动因素并将 p38MAPK-MK2 轴确定为可以保护骨骼并改善癌症幸存者生活质量的假定治疗靶点，从而改变了我们对化疗引起的骨质流失的理解。意义：衰老驱动化疗引起的骨质流失，而 p38MAPK 或 MK2 抑制剂可挽救这种骨质流失。这些发现可能会导致治疗引起的骨质流失，从而显着提高癌症幸存者的生活质量。