Li Boer, Lee Wen-Chih, Song Chao, Ye Ling, Abel E Dale, Long Fanxin
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA.
FASEB J. 2020 Aug;34(8):11058-11067. doi: 10.1096/fj.202000771R. Epub 2020 Jul 6.
Excessive bone resorption over bone formation is the root cause for bone loss leading to osteoporotic fractures. Development of new antiresorptive therapies calls for a holistic understanding of osteoclast differentiation and function. Although much has been learned about the molecular regulation of osteoclast biology, little is known about the metabolic requirement and bioenergetics during osteoclastogenesis. Here, we report that glucose metabolism through oxidative phosphorylation (OXPHOS) is the predominant bioenergetic pathway to support osteoclast differentiation. Meanwhile, increased lactate production from glucose, known as aerobic glycolysis when oxygen is abundant, is also critical for osteoclastogenesis. Genetic deletion of Glut1 in osteoclast progenitors reduces aerobic glycolysis without compromising OXPHOS, but nonetheless diminishes osteoclast differentiation in vitro. Glut1 deficiency in the progenitors leads to osteopetrosis due to fewer osteoclasts specifically in the female mice. Thus, Glut1-mediated glucose metabolism through both lactate production and OXPHOS is necessary for normal osteoclastogenesis.
骨吸收超过骨形成是导致骨质疏松性骨折的骨质流失的根本原因。开发新的抗吸收疗法需要全面了解破骨细胞的分化和功能。尽管我们已经对破骨细胞生物学的分子调控有了很多了解，但对于破骨细胞生成过程中的代谢需求和生物能量学却知之甚少。在此，我们报告通过氧化磷酸化（OXPHOS）进行的葡萄糖代谢是支持破骨细胞分化的主要生物能量途径。同时，葡萄糖产生的乳酸增加，在氧气充足时称为有氧糖酵解，对破骨细胞生成也至关重要。破骨细胞祖细胞中Glut1的基因缺失可减少有氧糖酵解而不影响OXPHOS，但仍会在体外减少破骨细胞的分化。祖细胞中Glut1的缺乏会导致骨质石化，特别是在雌性小鼠中，原因是破骨细胞较少。因此，Glut1介导的通过乳酸生成和OXPHOS的葡萄糖代谢对于正常的破骨细胞生成是必要的。
