Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence 50139, Italy.
Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Medical Genetics Unit, University of Florence, 50141 Florence, Italy.
Brain Behav Immun. 2023 May;110:348-364. doi: 10.1016/j.bbi.2023.03.013. Epub 2023 Mar 20.
Insulin growth factor-1 (IGF-1), an osteoclast-dependent osteolysis biomarker, contributes to metastatic bone cancer pain (MBCP), but the underlying mechanism is poorly understood. In mice, the femur metastasis caused by intramammary inoculation of breast cancer cells resulted in IGF-1 increase in femur and sciatic nerve, and IGF-1-dependent stimulus/non-stimulus-evoked pain-like behaviors. Adeno-associated virus-based shRNA selective silencing of IGF-1 receptor (IGF-1R) in Schwann cells, but not in dorsal root ganglion (DRG) neurons, attenuated pain-like behaviors. Intraplantar IGF-1 evoked acute nociception and mechanical/cold allodynia, which were reduced by selective IGF-1R silencing in DRG neurons and Schwann cells, respectively. Schwann cell IGF-1R signaling promoted an endothelial nitric oxide synthase-mediated transient receptor potential ankyrin 1 (TRPA1) activation and release of reactive oxygen species that, via macrophage-colony stimulating factor-dependent endoneurial macrophage expansion, sustained pain-like behaviors. Osteoclast derived IGF-1 initiates a Schwann cell-dependent neuroinflammatory response that sustains a proalgesic pathway that provides new options for MBCP treatment.
胰岛素样生长因子 1（IGF-1）是一种破骨细胞依赖性骨溶解生物标志物，导致转移性骨癌痛（MBCP），但其潜在机制尚不清楚。在小鼠中，乳腺癌细胞乳腺内接种引起的股骨转移导致股骨和坐骨神经中 IGF-1 增加，以及 IGF-1 依赖性刺激/非刺激诱发的痛觉样行为。腺相关病毒载体的 shRNA 选择性沉默施万细胞中的 IGF-1 受体（IGF-1R），但不沉默背根神经节（DRG）神经元中的 IGF-1R，可减轻痛觉样行为。足底注射 IGF-1 可诱发急性痛觉和机械/冷感觉过敏，DRG 神经元和施万细胞中 IGF-1R 的选择性沉默分别减轻了这些反应。施万细胞 IGF-1R 信号促进内皮型一氧化氮合酶介导的瞬时受体电位锚蛋白 1（TRPA1）激活和活性氧的释放，通过巨噬细胞集落刺激因子依赖性神经内膜巨噬细胞扩张，维持痛觉样行为。破骨细胞衍生的 IGF-1 引发施万细胞依赖性神经炎症反应，维持促痛觉通路，为 MBCP 的治疗提供了新的选择。
