MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα
MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERRα
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DOI：
10.1172/jci89935
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发表时间：
2017-06-30
影响因子：
15.9
通讯作者：
Park-Min, Kyung-Hyun
中科院分区：
文献类型：
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作者：
Bae, Seyeon;Lee, Min Joon;Park-Min, Kyung-Hyun
骨质疏松症是一种代谢性骨疾病，与骨强度受损和骨折风险增加有关。抑制骨吸收破骨细胞的分化是治疗骨质疏松症的有效策略。我们实验室和其他实验室先前的工作表明，MYC促进体外破骨细胞生成，但其潜在机制尚未完全了解。此外，破骨细胞表达的MYC在生理和病理性骨丢失中的体内重要性尚不清楚。在这里，我们已经证明，删除Myc在破骨细胞增加骨量和保护小鼠卵巢切除术诱导（OVX诱导）骨质疏松症。转录组学分析表明，MYC驱动破骨细胞分化过程中的代谢重编程，并作为代谢开关氧化状态的功能。我们确定了MYC在雌激素受体相关受体α（ERR α）转录诱导中的作用，ERR α是一种核受体，与活化T细胞的转录因子核因子c1（NFATc 1）合作驱动破骨细胞生成。因此，ERRa的药理学抑制减弱了OVX诱导的小鼠骨丢失。我们的研究结果强调了MYC/ERR α途径，该途径通过整合MYC/ERR α轴来驱动破骨细胞分化期间的代谢重编程，从而导致生理性和病理性骨丢失。
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 alpha (ERR alpha), a nuclear receptor that cooperates with the transcription factor nuclear factor of activated T cells, c1 (NFATc1) to drive osteoclastogenesis. Accordingly, pharmacological inhibition of ERRa attenuated OVX-induced bone loss in mice. Our findings highlight a MYC/ERR alpha pathway that contributes to physiological and pathological bone loss by integrating the MYC/ERR alpha axis to drive metabolic reprogramming during osteoclast differentiation.