破骨细胞
兰克尔
细胞生物学
骨吸收
多核
细胞融合
半胱氨酸蛋白酶
磷脂酰丝氨酸
半胱氨酸蛋白酶8
化学
合胞体
生物
细胞凋亡
激活剂(遗传学)
程序性细胞死亡
生物化学
细胞
内分泌学
磷脂
膜
体外
基因
作者
Brenda Krishnacoumar,M Stenzel,Hilal Garibagaoglu,Yasunori Omata,Rachel L. Sworn,Thea Hofmann,Natacha Ipseiz,Magdalena A. Czubala,Ulrike Steffen,Antonio Maccataio,Cornelia Stoll,Christina Böhm,Martin Herrmann,Stefan Uderhardt,Robert L. Jenkins,Philip R. Taylor,Anika Grüneboom,Mario M. Zaiss,Georg Schett,Gerhard Krönke,Carina Scholtysek
标识
DOI:10.1038/s41413-024-00338-4
摘要
Abstract Efficient cellular fusion of mononuclear precursors is the prerequisite for the generation of fully functional multinucleated bone-resorbing osteoclasts. However, the exact molecular factors and mechanisms controlling osteoclast fusion remain incompletely understood. Here we identify RANKL-mediated activation of caspase-8 as early key event during osteoclast fusion. Single cell RNA sequencing-based analyses suggested that activation of parts of the apoptotic machinery accompanied the differentiation of osteoclast precursors into mature multinucleated osteoclasts. A subsequent characterization of osteoclast precursors confirmed that RANKL-mediated activation of caspase-8 promoted the non-apoptotic cleavage and activation of downstream effector caspases that translocated to the plasma membrane where they triggered activation of the phospholipid scramblase Xkr8. Xkr8-mediated exposure of phosphatidylserine, in turn, aided cellular fusion of osteoclast precursors and thereby allowed generation of functional multinucleated osteoclast syncytia and initiation of bone resorption. Pharmacological blockage or genetic deletion of caspase-8 accordingly interfered with fusion of osteoclasts and bone resorption resulting in increased bone mass in mice carrying a conditional deletion of caspase-8 in mononuclear osteoclast precursors. These data identify a novel pathway controlling osteoclast biology and bone turnover with the potential to serve as target for therapeutic intervention during diseases characterized by pathologic osteoclast-mediated bone loss.
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