RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis

Yue, Zhiying; Niu, Xin; Zeng, Yuan; Qin, Qin; Jiang, Wenhao; Li, He; Gao, Jingduo; Ding, Yi; Liu, Yanxi; Xu, Ziwei; Li, Zhenxi; Yang, Zhengfeng; Li, Rong; Xue, Xiwen; Gao, Yankun; Fei, Yue; Zhang, Xiang H.-F.; Hu, Guohong; Wang, Yi; Li, Yang; Chen, Geng; Siwko, Stefan; Gartland, Alison; Wang, Ning; Xiao, Jianru; Liu, Mingyao; Luo, Jian

doi:10.1172/jci144579

Cited by 34 publications

(23 citation statements)

References 68 publications

(108 reference statements)

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“…This implies that MDA-MB-231CM induces osteoclast differentiation. A different study has shown that the CM of the BC cells recruits the osteoclast precursors, thereby increasing the quantity and activity of the osteoclasts in mice ( Yue et al, 2022 ). It has been indicated that the interaction between BC cells and bone microenvironment is involved in the complex molecular mechanisms involved in breast cancer bone metastasis.…”

Section: Discussionmentioning

confidence: 99%

The role played by ailanthone in inhibiting bone metastasis of breast cancer by regulating tumor-bone microenvironment through the RANKL-dependent pathway

Wang

Zhong

et al. 2023

Front. Pharmacol.

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Introduction: Bone metastasis of breast cancer (BC) is a process in which the disruption of the bone homeostatic microenvironment leads to an increase in osteoclast differentiation. Ailanthus altissima shows an inhibitory effect on osteoclast differentiation. Ailanthone (AIL) refers to a natural compound isolated from Ailanthus altissima, a Chinese herbal medicine, and has effective anti-tumor activity in numerous cell lines. Its impact on bone metastases for BC is yet unclear.Methods: We measured the effect of AIL on MDA-MB-231 cells by wound healing experiments, Transwell and colony formation experiment. Using the Tartrate-resistant Acid Phosphatase (TRAP) staining tests, filamentous (F-actin) staining and bone resorption test to detect the effect of AIL on the osteoclast cell differentiation of the Bone Marrow-derived Macrophages (BMMs), activated by the MDA-MB-231 cell Conditioned Medium (MDA-MB-231 CM) and the Receptor Activator of Nuclear factor-κB Ligand (RANKL),and to explore its possibility Mechanisms. In vivo experiments verified the effect of AIL on bone destruction in breast cancer bone metastasis model mice.Results:In vitro, AIL significantly decrease the proliferation, migration and infiltration abilities of MDA-MB-231 cells at a safe concentration, and also reduced the expression of genes and proteins involved in osteoclast formation in MDA-MB-231 cells. Osteoclast cell differentiation of the BMMs, activated by MDA-MB-231 CM and RANKL, were suppressed by AIL in the concentration-dependent manner. Additionally, it inhibits osteoclast-specific gene and protein expression. It was noted that AIL inhibited the expression of the osteoclast differentiation-related cytokines RANKL and interleukin-1β (IL-1β) that were secreted by the MDA-MB-231 cells after upregulating the Forkhead box protein 3 (FOXP3) expression. Furthermore, AIL also inhibits the expression of the Mitogen-Activated Protein Kinase (MAPK), Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), and Nuclear factor-κB Ligand (NF-κB) signaling pathways, which then suppresses the MDA-MB-231CM-induced development of Osteoclasts.Conclusion: Our study shows that AIL blocks osteoclast differentiation in the bone metastasis microenvironment by inhibiting cytokines secreted by BC cells, which may be a potential agent for the treatment of BC and its secondary bone metastasis.

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Section: Discussionmentioning

confidence: 99%

The role played by ailanthone in inhibiting bone metastasis of breast cancer by regulating tumor-bone microenvironment through the RANKL-dependent pathway

Wang

Zhong

et al. 2023

Front. Pharmacol.

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“…Also, in the paper by Yue et al. ( 44 ), LGR4-ECD was shown to hold therapeutic potential against breast cancer metastasis into bones. These studies demonstrate a significant and a tissue context-dependent therapeutic potential of LGR4-ECD, which is summarized in Figure 3 .…”

Section: Extracellular Domain Of Lgr4 As a Signaling Molecule And A P...mentioning

confidence: 97%

LGR4, a G Protein-Coupled Receptor With a Systemic Role: From Development to Metabolic Regulation

et al. 2022

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Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4/GPR48), a member of the GPCR (G protein-coupled receptors) superfamily, subfamily B, is a common intestinal crypt stem cell marker. It binds R-spondins/Norrin as classical ligands and plays a crucial role in Wnt signaling potentiation. Interaction between LGR4 and R-spondins initiates many Wnt-driven developmental processes, e.g., kidney, eye, or reproductive tract formation, as well as intestinal crypt (Paneth) stem cell pool maintenance. Besides the well-described role of LGR4 in development, several novel functions of this receptor have recently been discovered. In this context, LGR4 was indicated to participate in TGFβ and NFκB signaling regulation in hematopoietic precursors and intestinal cells, respectively, and found to be a new, alternative receptor for RANKL (Receptor Activator of NF kappa B Ligand) in bone cells. LGR4 inhibits the process of osteoclast differentiation, by antagonizing the interaction between RANK (Receptor Activator of NF kappa B) and its ligand-RANKL. It is also known to trigger anti-inflammatory responses in different tissues (liver, intestine, cardiac cells, and skin), serve as a sensor of the circadian clock in the liver, regulate adipogenesis and energy expenditure in adipose tissue and skeletal muscles, respectively. The extracellular domain of LGR4 (LGR4-ECD) has emerged as a potential new therapeutic for osteoporosis and cancer. LGR4 integrates different signaling pathways and regulates various cellular processes vital for maintaining whole-body homeostasis. Yet, the role of LGR4 in many cell types (e.g. pancreatic beta cells) and diseases (e.g., diabetes) remains to be elucidated. Considering the broad spectrum of LGR4 actions, this review aims to discuss both canonical and novel roles of LGR4, with emphasis on emerging research directions focused on this receptor.

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“…Moreover, breast cancer-derived factors support attachment and survival of disseminated tumor cells to the premetastatic niche in bone by inducing changes in bone mineral properties [93]. Similarly, R-spondin 2 (RSPO2) and RANKL, secreted from breast cancer cells, are involved in the recruitment of osteoclast progenitors and formation of osteoclastic premetastatic niche [94]. They bind to the LGR4 receptor and regulate the expression of Dickkopf-related protein 1 (DKK1), a soluble inhibitor of Wnt signaling.…”

Section: Early Stages Of Bone Metastasis and The Pre-metastatic Nichementioning

confidence: 99%

Muscle and Bone Defects in Metastatic Disease

Pauk

Saito

Hesse

et al. 2022

Curr Osteoporos Rep

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Purpose of Review The present review addresses most recently identified mechanisms implicated in metastasis-induced bone resorption and muscle-wasting syndrome, known as cachexia. Recent Findings Metastatic disease in bone and soft tissues is often associated with skeletal muscle defects. Recent studies have identified a number of secreted molecules and extracellular vesicles that contribute to cancer cell growth and metastasis leading to bone destruction and muscle atrophy. In addition, alterations in muscle microenvironment including dysfunctions in hepatic and mitochondrial metabolism have been implicated in cancer-induced regeneration defect and muscle loss. Moreover, we review novel in vitro and animal models including promising new drug candidates for bone metastases and cancer cachexia. Summary Preservation of bone health could be highly beneficial for maintaining muscle mass and function. Therefore, a better understanding of molecular pathways implicated in bone and muscle crosstalk in metastatic disease may provide new insights and identify new strategies to improve current anticancer therapeutics.

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RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis

Cited by 34 publications

References 68 publications

The role played by ailanthone in inhibiting bone metastasis of breast cancer by regulating tumor-bone microenvironment through the RANKL-dependent pathway

The role played by ailanthone in inhibiting bone metastasis of breast cancer by regulating tumor-bone microenvironment through the RANKL-dependent pathway

LGR4, a G Protein-Coupled Receptor With a Systemic Role: From Development to Metabolic Regulation

Muscle and Bone Defects in Metastatic Disease

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