Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone

Asano, Tatsuo; Okamoto, Kazuo; Nakai, Yoshihisa; Tsutsumi, Masanori; Muro, Ryunosuke; Suematsu, Ayako; Hashimoto, Kyoko; Okamura, Tadashi; Ehata, Shogo; Nitta, Takeshi; Takayanagi, Hiroshi

doi:10.1038/s42255-019-0104-1

Cited by 54 publications

(39 citation statements)

References 36 publications

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“…3),43), 44) To address this question, we generated mice in which the cleavage site of RANKL was deleted. 39), 45) The mice had no detectable soluble form of RANKL but a normal level of membranebound RANKL. 39),45) Surprisingly, the soluble RANKL-deficient mice exhibited no abnormalities in bone development, osteoclastogenesis, lymph node organogenesis, thymic epithelial cells, M cells or mammary gland development.…”

Section: Which Cells Express Rankl?mentioning

confidence: 99%

“…45) Bone metastasis of B16F10 melanoma cells injected into the heart was markedly reduced in cases of soluble RANKL deficiency. 45) Therefore, soluble RANKL is physiologically dispensable but involved in the acceleration of tumor metastasis to bone (Fig. 3).…”

Section: Which Cells Express Rankl?mentioning

confidence: 99%

“…39),45) Surprisingly, the soluble RANKL-deficient mice exhibited no abnormalities in bone development, osteoclastogenesis, lymph node organogenesis, thymic epithelial cells, M cells or mammary gland development. 45) We examined certain disease models including ovariectomy-induced osteoporosis and periodontitis, but there was no significant difference in the severity of the symptoms. 23), 45) The only difference found was in bone metastasis cancer models.…”

Section: Which Cells Express Rankl?mentioning

confidence: 99%

“…45) We examined certain disease models including ovariectomy-induced osteoporosis and periodontitis, but there was no significant difference in the severity of the symptoms. 23), 45) The only difference found was in bone metastasis cancer models. 45) Bone metastasis of B16F10 melanoma cells injected into the heart was markedly reduced in cases of soluble RANKL deficiency.…”

Section: Which Cells Express Rankl?mentioning

confidence: 99%

“…3). 45) In humans, the serum level of soluble RANKL has been shown to correlate with the prognosis of bone metastasis. RANKL has also been shown to be involved in the onset of certain malignant tumors, including mammary tumors, and in the regulation of anti-tumor immunity.…”

Section: Which Cells Express Rankl?mentioning

confidence: 99%

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Osteoimmunology — Bidirectional dialogue and inevitable union of the fields of bone and immunity —

Takayanagi

2020

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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Bone is a critically important part of the skeletal system that is essential for body support and locomotion. The immune system protects against pathogens and is active in host defense. These two seemingly distinct systems in fact interact with each other, share molecules and create a collaborative regulatory system called the "osteoimmune system". The most representative osteoimmune molecule is receptor activator of NF-5B ligand (RANKL), which plays multiple roles in the osteoimmune system under both physiological and pathological conditions such as rheumatoid arthritis and cancer metastasis to bone. Based on accumulating evidence for such mutual dependence, it is concluded that the relationship between bone and the immune system did not develop by accident but as a necessary consequence of evolution. Here I describe the history of and recent advances in osteoimmunology, providing a perspective in the contexts of both science and medicine.

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Section: Which Cells Express Rankl?mentioning

confidence: 99%

Section: Which Cells Express Rankl?mentioning

confidence: 99%

Section: Which Cells Express Rankl?mentioning

confidence: 99%

Section: Which Cells Express Rankl?mentioning

confidence: 99%

Section: Which Cells Express Rankl?mentioning

confidence: 99%

See 3 more Smart Citations

Osteoimmunology — Bidirectional dialogue and inevitable union of the fields of bone and immunity —

Takayanagi

2020

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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Vasorin as an actor of bone turnover?

Andrique,

Bonnet,

Dang

et al. 2024

Journal Cellular Physiology

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Bone diseases are increasing with aging populations and it is important to identify clues to develop innovative treatments. Vasn, which encodes vasorin (Vasn), a transmembrane protein involved in the pathophysiology of several organs, is expressed during the development in intramembranous and endochondral ossification zones. Here, we studied the impact of Vasn deletion on the osteoblast and osteoclast dialog through a cell Coculture model. In addition, we explored the bone phenotype of Vasn KO mice, either constitutive or tamoxifen‐inducible, or with an osteoclast‐specific deletion. First, we show that both osteoblasts and osteoclasts express Vasn. Second, we report that, in both KO mouse models but not in osteoclast‐targeted KO mice, Vasn deficiency was associated with an osteopenic bone phenotype, due to an imbalance in favor of osteoclastic resorption. Finally, through the Coculture experiments, we identify a dysregulation of the Wnt/β‐catenin pathway together with an increase in RANKL release by osteoblasts, which led to an enhanced osteoclast activity. This study unravels a direct role of Vasn in bone turnover, introducing a new biomarker or potential therapeutic target for bone pathologies.

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Glutathione peroxidase 8 expression on cancer cells and cancer‐associated fibroblasts facilitates lung cancer metastasis

Yuan

Jiang

et al. 2022

MedComm

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Lung cancer is the leading cause of cancer death worldwide, of which lung adenocarcinoma (LUAD) is the most common subtype. Metastasis is the major cause of poor prognosis and mortality for lung cancer patients, which urgently needs great efforts to be further explored. Herein, glutathione peroxidase 8 (GPX8) was identified as a novel potential pro‐metastatic gene in LUAD metastatic mice models from GEO database. GPX8 was highly expressed in tumor tissues, predicting poor prognosis in LUAD patients. Knockdown of GPX8 inhibited LUAD metastasis in vitro and in vivo, while it did not obviously affect tumor growth. Knockdown of GPX8 decreased the levels of p‐FAK and p‐Paxillin and disturbed the distribution of focal adhesion. Furthermore, GPX8 was overexpressed in cancer‐associated fibroblast (CAF) and associated with CAF infiltration in tumor microenvironment of lung cancer. GPX8 silence on fibroblasts suppressed lung cancer cell migration in the coculture system. BRD2 and RRD4 were the potential transcriptionally regulators for GPX8. Bromodomain extra‐terminal inhibitor JQ1 downregulated GPX8 expression and suppressed lung cancer cell migration. Our findings indicate that highly expressed GPX8 in lung cancer cells and fibroblasts functions as a pro‐metastatic factor in lung cancer. JQ1 is identified as a potential inhibitor against GPX8‐mediated lung cancer metastasis.

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Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone

Cited by 54 publications

References 36 publications

Osteoimmunology — Bidirectional dialogue and inevitable union of the fields of bone and immunity —

Osteoimmunology — Bidirectional dialogue and inevitable union of the fields of bone and immunity —

Vasorin as an actor of bone turnover?

Glutathione peroxidase 8 expression on cancer cells and cancer‐associated fibroblasts facilitates lung cancer metastasis

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