Mechanical Loading-Driven Tumor Suppression Is Mediated by Lrp5-Dependent and Independent Mechanisms

SIMPLE SUMMARY: Advanced breast cancer and prostate cancer metastasize to varying organs including the bone. We show here that mechanical loading to the knee suppresses tumor growth in the loaded bone and the non-loaded mammary pad. Although lipoprotein receptor-related protein 5 (Lrp5) in osteocytes is necessary to induce loading-driven bone formation, loading-driven tumor suppression is regulated by Lrp5-dependent and independent mechanisms. Lrp5 overexpression in osteocytes enhances tumor suppression, but without Lrp5 in osteocytes, mechanical loading elevates dopamine, chemerin, p53, and TNF-related apoptosis-inducing ligand (TRAIL) and reduces cholesterol and nexin. Their systemic changes contribute to inhibiting tumors without Lrp5. Osteoclast development is also inhibited by the load-driven regulation of chemerin and nexin. ABSTRACT: 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.