Sexual dimorphism of osteoclast reliance on mitochondrial oxidation of energy substrates in the mouse.
Sexual dimorphism of osteoclast reliance on mitochondrial oxidation of energy substrates in the mouse.
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DOI：
10.1172/jci.insight.174293
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发表时间：
2023-12-22
期刊：
影响因子：
8
通讯作者：
Long, Fanxin
中科院分区：
文献类型：
--
作者：
Song, Chao;Valeri, Arianna;Song, Fangfang;Ji, Xing;Liao, Xueyang;Marmo, Tyler;Seeley, Rebecca;Rutter, Jared;Long, Fanxin
破骨细胞专门从事骨吸收，对于骨重塑至关重要。先前的研究表明，破骨细胞拥有丰富的线粒体，并通过氧化磷酸化（OXPHOS）获取大部分能量。然而，破骨细胞中为 OXPHOS 提供能量的能量底物仍有待完全确定。在这里，我们发现破骨细胞分化与葡萄糖、谷氨酰胺和油酸的氧化增加有关。 RNA测序的转录组分析显示，在破骨细胞分化过程中，参与OXPHOS和线粒体脂肪酸氧化的基因显着上调。破骨细胞体外分化需要增加线粒体对长链脂肪酸的氧化。然而，通过删除破骨细胞祖细胞中的肉碱棕榈酰转移酶 1a (Cpt1a) 来阻断体内脂肪酸氧化，仅在雌性小鼠中损害破骨细胞形成。高脂肪饮食进一步保护了 Cpt1a 缺陷的雌性免受破骨细胞激活的影响。相反，尽管 Cpt1a 缺失，但无论膳食脂肪含量如何，雄性动物仍表现出正常的骨吸收。此外，同时删除线粒体丙酮酸载体1和Cpt1a，阻断破骨细胞谱系中葡萄糖和脂肪酸的线粒体氧化，未能阻止男性的骨吸收。因此，该研究揭示了女性体内破骨细胞中脂肪酸和葡萄糖线粒体氧化的特异性依赖性。
Osteoclasts specialize in bone resorption and are critical for bone remodeling. Previous studies have shown that osteoclasts possess abundant mitochondria and derive most energy through oxidative phosphorylation (OXPHOS). However, the energy substrates fueling OXPHOS in osteoclasts remain to be fully defined. Here, we showed that osteoclast differentiation was coupled with increased oxidation of glucose, glutamine, and oleate. Transcriptomic analyses with RNA sequencing revealed marked upregulation of genes participating in OXPHOS and mitochondrial fatty acid oxidation, during osteoclast differentiation. Increased mitochondrial oxidation of long-chain fatty acids was required for osteoclast differentiation in vitro. However, blocking fatty acid oxidation in vivo, by deletion of carnitine palmitoyltransferase 1a (Cpt1a) in osteoclast progenitors, impaired osteoclast formation only in the female mice. The Cpt1a-deficient females were further protected from osteoclast activation by a high-fat diet. The males, on the contrary, exhibited normal bone resorption despite Cpt1a deletion, regardless of the dietary fat content. Moreover, concurrent deletion of mitochondrial pyruvate carrier 1 and Cpt1a, blocking mitochondrial oxidation of both glucose and fatty acids in the osteoclast lineage, failed to impede bone resorption in the males. The study therefore uncovers a female-specific dependence on mitochondrial oxidation of fatty acids and glucose in osteoclasts in vivo.
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