MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

Bae, Seyeon; Lee, Min Joon; Mun, Se Hwan; Γιαννοπούλου, Ευγενία; Yong-Gonzalez, Vladimir; Cross, Justin R.; Murata, Koichi; Giguère, Vincent; Meulen, Marjolein C. H. van der; Park‐Min, Kyung‐Hyun

doi:10.1172/jci89935

Cited by 88 publications

(117 citation statements)

References 49 publications

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“…Recently, c-Myc, a vital target of β-catenin, was demonstrated to mediate RANK/RANKL signalling in an NFATc1-dependent or NFATc1-independent manner. The c-Myc/ERRα pathway exerts significant effects on osteoclast energy metabolism, which is essential for bone resorption [35][36][37]. Consistently, the expression levels of c-Myc and molecules downstream of RANK/RANKL signalling increased in our study.…”

Section: Discussionsupporting

confidence: 88%

Constitutive Activation of β-Catenin in Differentiated Osteoclasts Induces Bone Loss in Mice

Sui

Deng

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Activation of the Wnt/β-catenin signalling pathway has been widely investigated in bone biology and shown to promote bone formation. However, its specific effects on osteoclast differentiation have not been fully elucidated. Our study aimed to identify the role of β-catenin in osteoclastogenesis and bone homeostasis. Methods: In the present study, exon 3 in the β-catenin gene (Ctnnb1) allele encoding phosphorylation target serine/threonine residues was flanked by floxP sequences. We generated mice exhibiting conditional β-catenin activation (Ctsk-Cre;Ctnnb1^{flox(exon3)/+}, designated CA-β-catenin) by crossing Ctnnb1^{flox(exon3)/flox(exon3)} mice with osteoclast-specific Ctsk-Cre mice. Bone growth and bone mass were analysed by micro-computed tomography (micro-CT) and histomorphometry. To further examine osteoclast activity, osteoclasts were induced from bone marrow monocytes (BMMs) isolated from CA-β-catenin and Control mice in vitro. Osteoclast differentiation was detected by tartrate-resistant acid phosphatase (TRAP) staining, immunofluorescence staining and reverse transcription-quantitative PCR (RT–qPCR) analysis. Results: Growth retardation and low bone mass were observed in CA-β-catenin mice. Compared to controls, CA-β-catenin mice had significantly reduced trabecular bone numbers under growth plates as well as thinner cortical bones. Moreover, increased TRAP-positive osteoclasts were observed on the surfaces of trabecular bones and cortical bones in the CA-β-catenin mice; consistent results were observed in vitro. In the CA-β-catenin group, excessive numbers of osteoclasts were induced from BMMs, accompanied by the increased expression of osteoclast-associated marker genes. Conclusion: These results indicated that the constitutive activation of β-catenin in osteoclasts promotes osteoclast formation, resulting in bone loss.

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Section: Discussionsupporting

confidence: 88%

Constitutive Activation of β-Catenin in Differentiated Osteoclasts Induces Bone Loss in Mice

Sui

Deng

Liu

et al. 2018

Cell Physiol Biochem

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“…Taken together, the studies by Bae and colleagues (14) demonstrate that MYC functions as an important molecule mediating RANKL/RANK signaling in osteoclasts through mechanisms that are both dependent on and independent of NFATc1 ( Figure 1). Hence, these results argue that NFATc1 is not the only critical regulator of RANKL/ RANK-mediated signaling in osteoclasts.…”

Section: Resultsmentioning

confidence: 65%

“…Bae et al also evaluated the effect of the MYC/ERRα pathway on in vivo osteoclastogenesis and resorption (14). Specifically, the authors used the well-described ovariectomy model in mice to produce estrogen deficiency, which mimics postmenopausal osteoporosis and enhances osteoclastogenesis and bone resorption rates (21).…”

Section: Myc Contributes To Rankl/ Rank Signalingmentioning

confidence: 99%

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The many ways of osteoclast activation

Lorenzo¹

2017

Journal of Clinical Investigation

107

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“…In addition to angiogenesis, ERRα is mainly linked to tumor cell invasion [13][14][15]. ERRα is also highly expressed in skeletal tissues where it regulates osteoblast/osteoclast physiology [16][17][18][19]. In BM, we have reported that overexpression of ERRα in triple-negative BCa cells and castration-resistant prostate cancer cells results in either the inhibition or the activation of tumor cell progression in bone, respectively [20,21].…”

Section: Introductionmentioning

confidence: 99%

ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors

et al. 2018

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Bone is the most common metastatic site for breast cancer. Estrogen-related-receptor alpha (ERRα) has been implicated in cancer cell invasiveness. Here, we established that ERRα promotes spontaneous metastatic dissemination of breast cancer cells from primary mammary tumors to the skeleton. We carried out cohort studies, pharmacological inhibition, gain-offunction analyses in vivo and cellular and molecular studies in vitro to identify new biomarkers in breast cancer metastases. Meta-analysis of human primary breast tumors revealed that high ERRα expression levels were associated with bone but not lung metastases. ERRα expression was also detected in circulating tumor cells from metastatic breast cancer patients. ERRα overexpression in murine 4T1 breast cancer cells promoted spontaneous bone micro-metastases formation when tumor cells were inoculated orthotopically, whereas lung metastases occurred irrespective of ERRα expression level. In vivo, Rank was identified as a target for ERRα. That was confirmed in vitro in Rankl stimulated tumor cell invasion, in mTOR/pS6K phosphorylation, by transactivation assay, ChIP and bioinformatics analyses. Moreover, pharmacological inhibition of ERRα reduced primary tumor growth, bone micro-metastases formation and Rank expression in vitro and in vivo. Transcriptomic studies and meta-analysis confirmed a positive association between metastases and ERRα/RANK in breast cancer patients and also revealed a positive correlation between ERRα and BRCA1 mut carriers. Taken together, our results reveal a novel ERRα/RANK axis by which ERRα in primary breast cancer promotes early dissemination of cancer cells to bone. These findings suggest that ERRα may be a useful therapeutic target to prevent bone metastases.

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MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

Cited by 88 publications

References 49 publications

Constitutive Activation of β-Catenin in Differentiated Osteoclasts Induces Bone Loss in Mice

Constitutive Activation of β-Catenin in Differentiated Osteoclasts Induces Bone Loss in Mice

The many ways of osteoclast activation

ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors

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