Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba-city, Chiba, 260-8675, Japan.
Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba-city, Chiba, 260-8675, Japan.
Biochem Biophys Res Commun. 2020 Jul 5;527(4):874-880. doi: 10.1016/j.bbrc.2020.04.155. Epub 2020 May 16.
Bone homeostasis is maintained by bone remodeling, which involves continuous bone resorption by osteoclasts and bone formation by osteoblasts. Dysregulation of bone turnover, caused by osteoclast overactivation, causes destructive bone diseases. However, the mechanisms underlying the maintenance of osteoclast differentiation and activation are unclear. Herein, we examined the role of autophagy in the maintenance of osteoclast differentiation and maturation. We used in vitro and in vivo assays to evaluate relationships between mitochondrial activity and autophagy during osteoclast differentiation and maturation. Our results indicate that autophagy was enhanced during osteoclast differentiation and maturation, and autophagic activity was positively correlated with osteoclast activity and survival. Maintenance of mitochondrial function, which is critical during osteoclast differentiation and maturation, was controlled by autophagy. Continuous exposure of osteoclasts to glucocorticoids upregulated autophagic processes. Treatment with the autophagic inhibitor chloroquine suppressed prolonged survival of activated osteoclasts and attenuated excessive osteoclast activity. Our study shows that autophagy-dependent mitochondrial function plays an important role in osteoclast differentiation and maturation. Elucidating the mechanisms regulating autophagic activity in osteoclasts, and developing bone-tissue-specific inhibitors of autophagy, will lead to improved understanding of the pathologies involved in destructive bone diseases.
骨稳态由骨重建维持，骨重建涉及破骨细胞的持续骨吸收和成骨细胞的骨形成。破骨细胞过度激活导致骨转换失调，引起破坏性骨疾病。然而，破骨细胞分化和激活的维持机制尚不清楚。在此，我们研究了自噬在维持破骨细胞分化和成熟中的作用。我们使用体外和体内实验来评估骨细胞分化和成熟过程中线粒体活性与自噬之间的关系。结果表明，自噬在破骨细胞分化和成熟过程中增强，自噬活性与破骨细胞活性和存活呈正相关。自噬控制着破骨细胞分化和成熟过程中至关重要的线粒体功能的维持。持续暴露于糖皮质激素可上调自噬过程。自噬抑制剂氯喹处理抑制了激活的破骨细胞的长期存活，并减弱了破骨细胞的过度活性。我们的研究表明，自噬依赖性线粒体功能在破骨细胞分化和成熟中发挥着重要作用。阐明调节破骨细胞自噬活性的机制，并开发骨组织特异性自噬抑制剂，将有助于更好地理解涉及破坏性骨疾病的病理机制。
