Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC 27705, USA.
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC 27705, USA.
Sci Transl Med. 2023 Nov 29;15(724):eabo5217. doi: 10.1126/scitranslmed.abo5217.
Radiotherapy remains a common treatment modality for cancer despite skeletal complications. However, there are currently no effective treatments for radiation-induced bone loss, and the consequences of radiotherapy on skeletal progenitor cell (SPC) survival and function remain unclear. After radiation, leptin receptor-expressing cells, which include a population of SPCs, become localized to hypoxic regions of the bone and stabilize the transcription factor hypoxia-inducible factor-2α (HIF-2α), thus suggesting a role for HIF-2α in the skeletal response to radiation. Here, we conditionally knocked out HIF-2α in leptin receptor-expressing cells and their descendants in mice. Radiation therapy in littermate control mice reduced bone mass; however, HIF-2α conditional knockout mice maintained bone mass comparable to nonirradiated control animals. HIF-2α negatively regulated the number of SPCs, bone formation, and bone mineralization. To test whether blocking HIF-2α pharmacologically could reduce bone loss during radiation, we administered a selective HIF-2α inhibitor called PT2399 (a structural analog of which was recently FDA-approved) to wild-type mice before radiation exposure. Pharmacological inhibition of HIF-2α was sufficient to prevent radiation-induced bone loss in a single-limb irradiation mouse model. Given that ~90% of patients who receive a HIF-2α inhibitor develop anemia because of off-target effects, we developed a bone-targeting nanocarrier formulation to deliver the HIF-2α inhibitor to mouse bone, to increase on-target efficacy and reduce off-target toxicities. Nanocarrier-loaded PT2399 prevented radiation-induced bone loss in mice while reducing drug accumulation in the kidney. Targeted inhibition of HIF-2α may represent a therapeutic approach for protecting bone during radiation therapy.
尽管存在骨骼并发症，但放射疗法仍然是癌症的常见治疗方式。然而，目前尚无有效的治疗方法可用于治疗放射性骨丢失，并且放射治疗对骨骼祖细胞（SPC）存活和功能的影响仍不清楚。在放射治疗后，瘦素受体表达细胞（包括一群 SPC）定位于骨骼的缺氧区域，并稳定转录因子缺氧诱导因子-2α（HIF-2α），这表明 HIF-2α在骨骼对辐射的反应中起作用。在这里，我们在小鼠中条件性敲除了瘦素受体表达细胞及其后代中的 HIF-2α。在同窝对照小鼠中进行放射治疗会减少骨量；然而，HIF-2α 条件性敲除小鼠保持的骨量与未受照射的对照动物相当。HIF-2α 负调控 SPC 的数量、骨形成和骨矿化。为了测试在放射治疗期间是否可以通过阻断 HIF-2α 来减少骨丢失，我们在暴露于辐射之前向野生型小鼠施用了一种称为 PT2399 的选择性 HIF-2α 抑制剂（其结构类似物最近获得了 FDA 批准）。HIF-2α 的药理抑制足以预防单次照射小鼠模型中的放射诱导性骨丢失。鉴于约 90%接受 HIF-2α 抑制剂治疗的患者由于脱靶效应而出现贫血，我们开发了一种骨靶向纳米载体制剂，将 HIF-2α 抑制剂递送至小鼠骨骼，以提高靶标疗效并降低脱靶毒性。载纳米载体的 PT2399 可防止小鼠发生放射诱导性骨丢失，同时减少肾脏中的药物积累。靶向抑制 HIF-2α 可能代表一种在放射治疗期间保护骨骼的治疗方法。
