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Journal of Orthopaedic Surgery and Research

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Open Access 01-12-2023 | Bone Metastasis | Research Article

GPR84 potently inhibits osteoclastogenesis and alleviates osteolysis in bone metastasis of colorectal cancer

Authors: Li Jian, Long Shi-wei, Jing Dan, Wu Juan, Zheng Wei

Published in: Journal of Orthopaedic Surgery and Research | Issue 1/2023

Abstract

The expression of GPR84 in bone marrow-derived monocytes/macrophages (BMMs) can inhibit osteoclast formation; however, its role in bone metastasis of colorectal cancer (CRC) is still unknown. To investigate the effects of GPR84 on bone metastasis of CRC, the murine CRC cell line MC-38 was injected into tibial bone marrow. We found that the expression of GPR84 in BMMs was gradually downregulated during bone metastasis of CRC, and the activation of GPR84 significantly prevented osteoclastogenesis in the tumor microenvironment. Mechanistically, the MAPK pathway mediated the effects of GPR84 on osteoclast formation. Moreover, we found that IL-11 at least partly inhibited the expression of GPR84 in the tumor microenvironment through the inactivation of STAT1. Additionally, activation of GPR84 could prevent osteolysis during bone metastasis of CRC. Our results suggest that CRC cells downregulate the expression of GPR84 in BMMs to promote osteoclastogenesis in an IL-11-dependent manner. Thus, GPR84 could be a potential therapeutic target to attenuate bone destruction induced by CRC metastasis.

Bonnelye E, Juarez P. Targeting bone metastasis in cancers. Cancers (Basel). 2021. https://doi.org/10.3390/cancers13174490.CrossRef

Aielli F, Ponzetti M, Rucci N. Bone metastasis pain, from the bench to the bedside. Int J Mol Sci. 2019. https://doi.org/10.3390/ijms20020280.CrossRef

Pulido C, Vendrell I, Ferreira AR, et al. Bone metastasis risk factors in breast cancer. Ecancermedicalscience. 2017;11:715. https://doi.org/10.3332/ecancer.2017.715.CrossRef

MacDonald IJ, Tsai HC, Chang AC, et al. Melatonin inhibits osteoclastogenesis and osteolytic bone metastasis: implications for osteoporosis. Int J Mol Sci. 2021. https://doi.org/10.3390/ijms22179435.CrossRef

Vicic I, Belev B. The pathogenesis of bone metastasis in solid tumors: a review. Croat Med J. 2021;62:270–82.CrossRef

Cheng X, Wei J, Ge Q, et al. The optimized drug delivery systems of treating cancer bone metastatic osteolysis with nanomaterials. Drug Deliv. 2021;28:37–53. https://doi.org/10.1080/10717544.2020.1856225.CrossRef

Chengling L, Yulin Z, Xiaoyu X, et al. miR-325-3p, a novel regulator of osteoclastogenesis in osteolysis of colorectal cancer through targeting S100A4. Mol Med. 2021;27:23. https://doi.org/10.1186/s10020-021-00282-7.CrossRef

Chen X, Wang Z, Duan N, et al. Osteoblast-osteoclast interactions. Connect Tissue Res. 2018;59:99–107. https://doi.org/10.1080/03008207.2017.1290085.CrossRef

Johnson RW, Suva LJ. Hallmarks of bone metastasis. Calcif Tissue Int. 2018;102:141–51. https://doi.org/10.1007/s00223-017-0362-4.CrossRef

10.

Kodama J, Kaito T. Osteoclast multinucleation: review of current literature. Int J Mol Sci. 2020. https://doi.org/10.3390/ijms21165685.CrossRef

11.

Liang M, Ma Q, Ding N, et al. IL-11 is essential in promoting osteolysis in breast cancer bone metastasis via RANKL-independent activation of osteoclastogenesis. Cell Death Dis. 2019;10:353. https://doi.org/10.1038/s41419-019-1594-1.CrossRef

12.

Liu N, Wang Y, Li T, et al. G-protein coupled receptors (GPCRs): signaling pathways, characterization, and functions in insect physiology and toxicology. Int J Mol Sci. 2021. https://doi.org/10.3390/ijms22105260.CrossRef

13.

Tang X, Jin R, Qu G, et al. GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the Galphaq-p63RhoGEF-Rho GTPase pathway. Cancer Res. 2013;73:6206–18. https://doi.org/10.1158/0008-5472.CAN-13-1049.CrossRef

14.

Majumder M, Nandi P, Omar A, et al. EP4 as a therapeutic target for aggressive human breast cancer. Int J Mol Sci. 2018. https://doi.org/10.3390/ijms19041019.CrossRef

15.

Rong YM, Huang XM, Fan DJ, et al. Overexpression of G protein-coupled receptor 31 as a poor prognosticator in human colorectal cancer. World J Gastroenterol. 2018;24:4679–90. https://doi.org/10.3748/wjg.v24.i41.4679.CrossRef

16.

Wang J, Sun Y, Tomura H, et al. Ovarian cancer G-protein-coupled receptor 1 induces the expression of the pain mediator prostaglandin E2 in response to an acidic extracellular environment in human osteoblast-like cells. Int J Biochem Cell Biol. 2012;44:1937–41. https://doi.org/10.1016/j.biocel.2012.07.015.CrossRef

17.

Chen L, Wang Y, Lu X, et al. miRNA-7062–5p promoting bone resorption after bone metastasis of colorectal cancer through inhibiting GPR65. Front Cell Dev Biol. 2021;9:681968. https://doi.org/10.3389/fcell.2021.681968.CrossRef

18.

Sasaki SI, Zhang D, Iwabuchi S, et al. Crucial contribution of GPR56/ADGRG1, expressed by breast cancer cells, to bone metastasis formation. Cancer Sci. 2021. https://doi.org/10.1111/cas.15150.CrossRef

19.

Park JW, Yoon HJ, Kang WY, et al. G protein-coupled receptor 84 controls osteoclastogenesis through inhibition of NF-kappaB and MAPK signaling pathways. J Cell Physiol. 2018;233:1481–9. https://doi.org/10.1002/jcp.26035.CrossRef

20.

Yonezawa T, Kurata R, Yoshida K, et al. Free fatty acids-sensing G protein-coupled receptors in drug targeting and therapeutics. Curr Med Chem. 2013;20:3855–71. https://doi.org/10.2174/09298673113209990168.CrossRef

21.

Zi-Chen G, Jin Q, Yi-Na Z, et al. Colorectal cancer cells promote osteoclastogenesis and bone destruction through regulating EGF/ERK/CCL3 pathway. 2020. Biosci Rep. https://doi.org/10.1042/BSR20201175.

22.

Miyawaki A, Iizuka Y, Sugino H, et al. IL-11 prevents IFN-gamma-induced hepatocyte death through selective downregulation of IFN-gamma/STAT1 signaling and ROS scavenging. PLoS ONE. 2019;14:e0211123. https://doi.org/10.1371/journal.pone.0211123.CrossRef

23.

Jiang P, Gao W, Ma T, et al. CD137 promotes bone metastasis of breast cancer by enhancing the migration and osteoclast differentiation of monocytes/macrophages. Theranostics. 2019;9:2950–66. https://doi.org/10.7150/thno.29617.CrossRef

24.

Guo Y, Tiedemann K, Khalil JA, et al. Osteoclast precursors acquire sensitivity to breast cancer derived factors early in differentiation. Bone. 2008;43:386–93. https://doi.org/10.1016/j.bone.2008.03.026.CrossRef

25.

Kim B, Kim H, Jung S, et al. A CTGF-RUNX2-RANKL axis in breast and prostate cancer cells promotes tumor progression in bone. J Bone Miner Res. 2020;35:155–66. https://doi.org/10.1002/jbmr.3869.CrossRef

26.

Okito A, Nakahama K, Akiyama M, et al. Involvement of the G-protein-coupled receptor 4 in RANKL expression by osteoblasts in an acidic environment. Biochem Biophys Res Commun. 2015;458:435–40. https://doi.org/10.1016/j.bbrc.2015.01.142.CrossRef

27.

Cornish J, MacGibbon A, Lin JM, et al. Modulation of osteoclastogenesis by fatty acids. Endocrinology. 2008;149:5688–95. https://doi.org/10.1210/en.2008-0111.CrossRef

28.

Cai WL, Huang WD, Li B, et al. microRNA-124 inhibits bone metastasis of breast cancer by repressing Interleukin-11. Mol Cancer. 2018;17:9. https://doi.org/10.1186/s12943-017-0746-0.CrossRef

29.

Maroni P, Bendinelli P, Ferraretto A, et al. Interleukin 11 (IL-11): ROLE(s) in Breast Cancer Bone Metastases. Biomedicines. 2021. https://doi.org/10.3390/biomedicines9060659.CrossRef

30.

Chen Z, Chen X, Xie R, et al. DANCR promotes metastasis and proliferation in bladder cancer cells by enhancing IL-11-STAT3 signaling and CCND1 expression. Mol Ther. 2019;27:326–41. https://doi.org/10.1016/j.ymthe.2018.12.015.CrossRef

31.

Ren L, Wang X, Dong Z, et al. Bone metastasis from breast cancer involves elevated IL-11 expression and the gp130/STAT3 pathway. Med Oncol. 2013;30:634. https://doi.org/10.1007/s12032-013-0634-4.CrossRef

32.

Ryan N, Anderson K, Volpedo G, et al. STAT1 inhibits T-cell exhaustion and myeloid derived suppressor cell accumulation to promote antitumor immune responses in head and neck squamous cell carcinoma. Int J Cancer. 2020;146:1717–29. https://doi.org/10.1002/ijc.32781.CrossRef

33.

Jiang L, Liu JY, Shi Y, et al. MTMR2 promotes invasion and metastasis of gastric cancer via inactivating IFNgamma/STAT1 signaling. J Exp Clin Cancer Res. 2019;38:206. https://doi.org/10.1186/s13046-019-1186-z.CrossRef

34.

Huang S, Bucana CD, Van Arsdall M, et al. Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells. Oncogene. 2002;21:2504–12. https://doi.org/10.1038/sj.onc.1205341.CrossRef

35.

Takagi T, Inoue H, Takahashi N, et al. Sulforaphane inhibits osteoclast differentiation by suppressing the cell-cell fusion molecules DC-STAMP and OC-STAMP. Biochem Biophys Res Commun. 2017;483:718–24. https://doi.org/10.1016/j.bbrc.2016.12.075.CrossRef

Title: GPR84 potently inhibits osteoclastogenesis and alleviates osteolysis in bone metastasis of colorectal cancer
Authors: Li Jian
Long Shi-wei
Jing Dan
Wu Juan
Zheng Wei
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Bone Metastasis
Colorectal Cancer
Colorectal Cancer
Published in: Journal of Orthopaedic Surgery and Research / Issue 1/2023
Electronic ISSN: 1749-799X
DOI: https://doi.org/10.1186/s13018-022-03473-y

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GPR84 potently inhibits osteoclastogenesis and alleviates osteolysis in bone metastasis of colorectal cancer

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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