Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone. Presently, no effective countermeasure exists, and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity. The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy. Our studies revealed that P7C3 repressed ionizing radiation (IR)-induced osteoclastic activity, inhibited adipogenesis, and promoted osteoblastogenesis and mineral deposition in vitro. We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened, osteoporotic bone. However, the administration of P7C3 significantly inhibited osteoclastic activity, lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area, architecture, and mechanical strength. Our findings revealed significant enhancement of cellular macromolecule metabolic processes, myeloid cell differentiation, and the proteins LRP-4, TAGLN, ILK, and Tollip, with downregulation of GDF-3, SH2B1, and CD200. These proteins are key in favoring osteoblast over adipogenic progenitor differentiation, cell matrix interactions, and shape and motility, facilitating inflammatory resolution, and suppressing osteoclastogenesis, potentially via Wnt/β-catenin signaling. A concern was whether P7C3 afforded similar protection to cancer cells. Preliminarily, and remarkably, at the same protective P7C3 dose, a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro. Together, these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy, leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications. Our data uncover a new approach for the prevention of radiation-induced bone damage, and further work is needed to investigate its ability to selectively drive cancer cell death.

放射治疗是癌症治疗的重要组成部分，但可能导致周围骨骼和其他健康骨骼发生骨质疏松症和病理性不全性骨折。目前，尚无有效的对策，电离辐射引起的骨损伤仍然是疼痛和发病的重要根源。本研究的目的是研究一种名为 P7C3 的小分子氨丙基咔唑作为一种新型辐射防护策略。我们的研究表明，P7C3 可抑制电离辐射 (IR) 诱导的破骨细胞活性，抑制脂肪生成，并促进体外成骨细胞生成和矿物质沉积。我们还证明，啮齿类动物在体内暴露于临床相当的大分割水平的IR后，会出现骨质疏松的骨骼。然而，P7C3的施用显着抑制破骨细胞活性，脂质形成和骨髓肥胖，并减轻组织损失，使骨骼保持其面积、结构和机械强度。我们的研究结果表明，细胞大分子代谢过程、骨髓细胞分化以及蛋白质 LRP-4、TAGLN、ILK 和 Tollip 显着增强，同时 GDF-3、SH2B1 和 CD200 下调。这些蛋白质是有利于成骨细胞而不是脂肪形成祖细胞分化、细胞基质相互作用、形状和运动、促进炎症消退和抑制破骨细胞生成的关键，可能通过 Wnt/β-连环蛋白信号传导。一个问题是 P7C3 是否为癌细胞提供类似的保护。值得注意的是，在相同的 P7C3 保护剂量下，体外发现三阴性乳腺癌和骨肉瘤细胞代谢活性显着降低。总之，这些结果表明 P7C3 是以前未被发现的脂肪成骨祖细胞谱系定向的关键调节因子，并且可以作为一种新型多功能治疗策略，使 IR 成为有效的临床工具，同时降低 IR 后不良并发症的风险。我们的数据揭示了一种预防辐射引起的骨损伤的新方法，需要进一步研究其选择性驱动癌细胞死亡的能力。使 IR 成为一种有效的临床工具，同时降低 IR 后不良并发症的风险。我们的数据揭示了一种预防辐射引起的骨损伤的新方法，需要进一步研究其选择性驱动癌细胞死亡的能力。使 IR 成为一种有效的临床工具，同时降低 IR 后不良并发症的风险。我们的数据揭示了一种预防辐射引起的骨损伤的新方法，需要进一步研究其选择性驱动癌细胞死亡的能力。