Mechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone. However, whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown. We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells. The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis, markedly reduced the progression of the brain tumors. The simultaneous application of fluphenazine (FP), an antipsychotic dopamine modulator, enhanced tumor suppression. Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2, respectively. Notably, dopamine downregulated Lrp5 via DRD1 in tumor cells. A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven, dopamine-mediated tumor suppression. The silencing of Lrp5 reduced CCN4, and the administration of CCN4 elevated oncogenic genes such as MMP9, Runx2, and Snail. In summary, this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1, indicating the possibility of developing an adjuvant bone-mediated loading therapy.

已知对骨骼的机械加载有益于骨骼的稳态，并有助于抑制肿瘤在加载的骨骼中引起的骨溶解。然而，尚不清楚负荷到后肢负重能抑制大脑中远处的肿瘤生长。我们通过集中研究对肿瘤细胞中Lrp5介导的Wnt信号和多巴胺的反应，研究了使用脑肿瘤小鼠模型进行骨骼到大脑机械转导的可能性。结果表明，在胫骨中加载高水平的酪氨酸羟化酶（一种多巴胺合成中的限速酶），可显着降低脑肿瘤的进展。同时应用抗精神病药多巴胺调节剂氟奋乃静（FP）可增强肿瘤抑制作用。多巴胺和FP分别通过多巴胺受体DRD1和DRD2发挥抗肿瘤作用。值得注意的是，多巴胺通过DRD1在肿瘤细胞中下调Lrp5。细胞因子阵列分析表明，CCN4的减少对于负荷驱动，多巴胺介导的肿瘤抑制至关重要。Lrp5的沉默降低了CCN4，并且给予CCN4增强了致癌基因，例如MMP9，Runx2和Snail。总而言之，这项研究表明机械负荷通过DRD1抑制Lrp5-CCN4轴，从而调节多巴胺能信号传导并远程抑制脑肿瘤，表明开发辅助骨介导负荷治疗的可能性。并给予CCN4增强的致癌基因，例如MMP9，Runx2和Snail。总而言之，这项研究表明机械负荷通过DRD1抑制Lrp5-CCN4轴，从而调节多巴胺能信号传导并远程抑制脑肿瘤，表明开发辅助骨介导负荷治疗的可能性。并给予CCN4增强的致癌基因，例如MMP9，Runx2和Snail。总而言之，这项研究表明机械负荷通过DRD1抑制Lrp5-CCN4轴，从而调节多巴胺能信号传导并远程抑制脑肿瘤，表明开发辅助骨介导负荷治疗的可能性。