Yang Biao, Su Yuangang, Han Shuai, Chen Runfeng, Sun Ran, Rong Kewei, Long Feng, Teng Hailong, Zhao Jinmin, Liu Qian, Qin An
Guangxi Key Laboratory of Regenerative Medicine, Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, Guangxi, China.
Research Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China.
Front Pharmacol. 2022 Sep 30;13:980678. doi: 10.3389/fphar.2022.980678. eCollection 2022.
Osteoclasts undergo active metabolic reprogramming to acquire the energy needed during differentiation and bone resorption. Compared with immature osteoclasts, mature osteoclasts comprise higher levels of electron transport chain enzymes and more metabolically active mitochondria. Of all energy metabolism pathways, oxidative phosphorylation is considered to be the most efficient in supplying energy to osteoclasts. We found that the malate-aspartate shuttle inhibitor aminooxyacetic acid hemihydrochloride inhibits osteoclastogenesis and bone resorption by inhibiting exchange of reducing equivalents between the cytosol and the mitochondrial matrix and attenuating mitochondrial oxidative phosphorylation . The weakening of the oxidative phosphorylation pathway resulted in reduced mitochondrial function and inadequate energy supply along with reduced reactive oxygen species production. Furthermore, treatment with aminooxyacetic acid hemihydrochloride helped recover bone loss in ovariectomized mice. Our findings highlight the potential of interfering with the osteoclast intrinsic energy metabolism pathway as a treatment for osteoclast-mediated osteolytic diseases.
破骨细胞会经历活跃的代谢重编程，以获取分化和骨吸收过程中所需的能量。与未成熟破骨细胞相比，成熟破骨细胞含有更高水平的电子传递链酶和代谢活性更强的线粒体。在所有能量代谢途径中，氧化磷酸化被认为是为破骨细胞提供能量最有效的途径。我们发现，苹果酸 - 天冬氨酸穿梭抑制剂半盐酸氨氧乙酸通过抑制胞质溶胶与线粒体基质之间还原当量的交换并减弱线粒体氧化磷酸化，从而抑制破骨细胞生成和骨吸收。氧化磷酸化途径的减弱导致线粒体功能降低、能量供应不足以及活性氧生成减少。此外，用半盐酸氨氧乙酸治疗有助于恢复去卵巢小鼠的骨质流失。我们的研究结果凸显了干扰破骨细胞内在能量代谢途径作为治疗破骨细胞介导的溶骨性疾病的潜力。
