Feng Yan, Liu Shengzhi, Zha Rongrong, Sun Xun, Li Kexin, Robling Alexander, Li Baiyan, Yokota Hiroki
Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
Cancers (Basel). 2021 Jan 13;13(2):267. doi: 10.3390/cancers13020267.
Bone is mechanosensitive and lipoprotein receptor-related protein 5 (Lrp5)-mediated Wnt signaling promotes loading-driven bone formation. While mechanical loading can suppress tumor growth, the question is whether Lrp5 mediates loading-driven tumor suppression. Herein, we examined the effect of Lrp5 using osteocyte-specific Lrp5 conditional knockout mice. All mice presented noticeable loading-driven tumor suppression in the loaded tibia and non-loaded mammary pad. The degree of suppression was more significant in wild-type than knockout mice. In all male and female mice, knee loading reduced cholesterol and elevated dopamine. It reduced tumor-promoting nexin, which was elevated by cholesterol and reduced by dopamine. By contrast, it elevated p53, TNF-related apoptosis-inducing ligand (TRAIL), and chemerin, and they were regulated reversely by dopamine and cholesterol. Notably, Lrp5 overexpression in osteocytes enhanced tumor suppression, and osteoclast development was inhibited by chemerin. Collectively, this study identified Lrp5-dependent and independent mechanisms for tumor suppression. Lrp5 in osteocytes contributed to the loaded bone, while the Lrp5-independent regulation of dopamine- and cholesterol-induced systemic suppression.
骨骼具有机械敏感性，脂蛋白受体相关蛋白5（Lrp5）介导的Wnt信号传导促进负荷驱动的骨形成。虽然机械负荷可抑制肿瘤生长，但问题是Lrp5是否介导负荷驱动的肿瘤抑制作用。在此，我们使用骨细胞特异性Lrp5条件性敲除小鼠研究了Lrp5的作用。所有小鼠在加载的胫骨和未加载的乳腺垫中均表现出明显的负荷驱动的肿瘤抑制作用。野生型小鼠的抑制程度比敲除小鼠更显著。在所有雄性和雌性小鼠中，膝关节负荷降低了胆固醇水平并提高了多巴胺水平。它降低了由胆固醇升高并由多巴胺降低的肿瘤促进因子Nexin。相比之下，它提高了p53、肿瘤坏死因子相关凋亡诱导配体（TRAIL）和chemerin的水平，并且它们受到多巴胺和胆固醇的反向调节。值得注意的是，骨细胞中Lrp5的过表达增强了肿瘤抑制作用，并且chemerin抑制了破骨细胞的发育。总的来说，这项研究确定了Lrp5依赖性和非依赖性的肿瘤抑制机制。骨细胞中的Lrp5有助于负荷的骨骼，而多巴胺和胆固醇诱导的全身抑制作用则通过不依赖Lrp5的调节来实现。
