MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα
Seyeon Bae, … , Marjolein van der Meulen, Kyung-Hyun Park-Min
Seyeon Bae, … , Marjolein van der Meulen, Kyung-Hyun Park-Min
Published May 22, 2017
Citation Information: J Clin Invest. 2017;127(7):2555-2568. https://doi.org/10.1172/JCI89935.
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Research Article Bone biology

MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα

Abstract

Osteoporosis is a metabolic bone disorder associated with compromised bone strength and an increased risk of fracture. Inhibition of the differentiation of bone-resorbing osteoclasts is an effective strategy for the treatment of osteoporosis. Prior work by our laboratory and others has shown that MYC promotes osteoclastogenesis in vitro, but the underlying mechanisms are not well understood. In addition, the in vivo importance of osteoclast-expressed MYC in physiological and pathological bone loss is not known. Here, we have demonstrated that deletion of Myc in osteoclasts increases bone mass and protects mice from ovariectomy-induced (OVX-induced) osteoporosis. Transcriptomic analysis revealed that MYC drives metabolic reprogramming during osteoclast differentiation and functions as a metabolic switch to an oxidative state. We identified a role for MYC action in the transcriptional induction of estrogen receptor–related receptor α (ERRα), a nuclear receptor that cooperates with the transcription factor nuclear factor of activated T cells, c1 (NFATc1) to drive osteoclastogenesis. Accordingly, pharmacological inhibition of ERRα attenuated OVX-induced bone loss in mice. Our findings highlight a MYC/ERRα pathway that contributes to physiological and pathological bone loss by integrating the MYC/ERRα axis to drive metabolic reprogramming during osteoclast differentiation.

Authors

Seyeon Bae, Min Joon Lee, Se Hwan Mun, Eugenia G. Giannopoulou, Vladimir Yong-Gonzalez, Justin R. Cross, Koichi Murata, Vincent Giguère, Marjolein van der Meulen, Kyung-Hyun Park-Min

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Figure 3

MYC deficiency impairs mitochondrial respiration during osteoclast differentiation.

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MYC deficiency impairs mitochondrial respiration during osteoclast diffe...
Control (MYCWT) and MYC-deficient (MYCΔM) OCPs were stimulated with RANKL (50 ng/ml) for 2 days. (A) Scatterplot of global gene expression profiles of MYCWT and MYCΔM OCPs derived from RNA-seq analysis. (B) GSEA of RANKL-stimulated MYCΔM OCPs, with genes ranked on the basis of expression in MYCΔM OCPs relative to that in MYCWT OCPs, showing the distribution of genes in the oxidative phosphorylation gene set against the ranked list of the genes from the RNA-seq analysis. (C) Heatmap of RNA-seq FPKM values for genes involved in oxidative phosphorylation in MYCWT and MYCΔM OCPs following RANKL stimulation for 2 days. RNA-seq data from 2 biological replicates were used. D0, day 0 without RANKL stimulation; D2, day 2 following RANKL stimulation; Min, minimum; Max, maximum. (D and E) Mitochondrial function was assessed by real-time OCR measurement after sequential treatment of compounds modulating mitochondrial function. The OCR was normalized to the relative amount of DNA. (D) Representative time course data. (E) Assessment of mitochondrial activity as described in Supplemental Figure 9 (n = 3). (F) Measurements of mitochondrial mass using MitoTracker Red with flow cytometry (n = 3). (G) The basal OCR was measured with mock-infected or MYC-transduced MYC-deficient OCPs stimulated with RANKL (50 ng/ml) for 2 days (n = 3). All data are shown as the mean ± SEM. *P < 0.05, by 2-way ANOVA with Tukey’s post-hoc test.