Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-05-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-021-00144-2 |
| _version_ | 1818833105481367552 |
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| author | Yao Fan Rongrong Zha Tomohiko Sano Xinyu Zhao Shengzhi Liu Mark D. Woollam Di Wu Xun Sun Kexin Li Motoki Egi Fangjia Li Kazumasa Minami Amanda P. Siegel Takashi Horiuchi Jing Liu Mangilal Agarwal Akihiro Sudo Harikrishna Nakshatri Bai-Yan Li Hiroki Yokota |
| author_facet | Yao Fan Rongrong Zha Tomohiko Sano Xinyu Zhao Shengzhi Liu Mark D. Woollam Di Wu Xun Sun Kexin Li Motoki Egi Fangjia Li Kazumasa Minami Amanda P. Siegel Takashi Horiuchi Jing Liu Mangilal Agarwal Akihiro Sudo Harikrishna Nakshatri Bai-Yan Li Hiroki Yokota |
| author_sort | Yao Fan |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-19T02:13:38Z |
| format | Article |
| id | doaj.art-b94e221f83104393a856d0b1f88dbe7e |
| institution | Directory Open Access Journal |
| issn | 2095-6231 |
| language | English |
| last_indexed | 2024-12-19T02:13:38Z |
| publishDate | 2021-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj.art-b94e221f83104393a856d0b1f88dbe7e2022-12-21T20:40:33ZengNature Publishing GroupBone Research2095-62312021-05-019111010.1038/s41413-021-00144-2Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4Yao Fan0Rongrong Zha1Tomohiko Sano2Xinyu Zhao3Shengzhi Liu4Mark D. Woollam5Di Wu6Xun Sun7Kexin Li8Motoki Egi9Fangjia Li10Kazumasa Minami11Amanda P. Siegel12Takashi Horiuchi13Jing Liu14Mangilal Agarwal15Akihiro Sudo16Harikrishna Nakshatri17Bai-Yan Li18Hiroki Yokota19Department of Phamacology, School of Pharmacy, Harbin Medical UniversityDepartment of Phamacology, School of Pharmacy, Harbin Medical UniversityDepartment of Biomedical Engineering, Indiana University Purdue University IndianapolisDepartment of Biomedical Engineering, Indiana University Purdue University IndianapolisDepartment of Biomedical Engineering, Indiana University Purdue University IndianapolisDepartment of Chemistry and Chemical Biology, Indiana University Purdue University IndianapolisDepartment of Phamacology, School of Pharmacy, Harbin Medical UniversityDepartment of Phamacology, School of Pharmacy, Harbin Medical UniversityDepartment of Phamacology, School of Pharmacy, Harbin Medical UniversityDepartment of Biomedical Engineering, Indiana University Purdue University IndianapolisDepartment of Physics, Indiana University Purdue University IndianapolisDepartment of Radiation Oncology, Osaka University Graduate School of MedicineDepartment of Chemistry and Chemical Biology, Indiana University Purdue University IndianapolisGraduate School of Engineering, Mie UniversityDepartment of Physics, Indiana University Purdue University IndianapolisIntegrative Nanosystems Development Institute, Indiana University Purdue University IndianapolisDepartment of Orthopedic Surgery, Mie UniversitySimon Cancer Center, Indiana University School of MedicineDepartment of Phamacology, School of Pharmacy, Harbin Medical UniversityDepartment of Phamacology, School of Pharmacy, Harbin Medical UniversityAbstract 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.https://doi.org/10.1038/s41413-021-00144-2 |
| spellingShingle | Yao Fan Rongrong Zha Tomohiko Sano Xinyu Zhao Shengzhi Liu Mark D. Woollam Di Wu Xun Sun Kexin Li Motoki Egi Fangjia Li Kazumasa Minami Amanda P. Siegel Takashi Horiuchi Jing Liu Mangilal Agarwal Akihiro Sudo Harikrishna Nakshatri Bai-Yan Li Hiroki Yokota Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4 Bone Research |
| title | Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4 |
| title_full | Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4 |
| title_fullStr | Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4 |
| title_full_unstemmed | Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4 |
| title_short | Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4 |
| title_sort | mechanical tibial loading remotely suppresses brain tumors by dopamine mediated downregulation of ccn4 |
| url | https://doi.org/10.1038/s41413-021-00144-2 |
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