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Caspase-8 promotes scramblase-mediated phosphatidylserine exposure and fusion of osteoclast precursors

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Titel: Caspase-8 promotes scramblase-mediated phosphatidylserine exposure and fusion of osteoclast precursors
Autoren: Brenda Krishnacoumar, Martin 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 H. Jenkins, Philip R. Taylor, Anika Grüneboom, Mario M. Zaiss, Georg Schett, Gerhard Krönke, Carina Scholtysek
Quelle: Bone Res
Bone Research, Vol 12, Iss 1, Pp 1-10 (2024)
Verlagsinformationen: Springer Science and Business Media LLC, 2024.
Publikationsjahr: 2024
Schlagwörter: 0301 basic medicine, Caspase 8, 0303 health sciences, QH301-705.5, Physiology, Bone Resorption/pathology [MeSH], Osteoclasts/metabolism [MeSH], Mice, Inbred C57BL [MeSH], Cell Differentiation [MeSH], Cell Fusion [MeSH], Caspase 8/metabolism [MeSH], Animals [MeSH], 631/443, Caspase 8/genetics [MeSH], Mice [MeSH], Article, Phosphatidylserines/metabolism [MeSH], Phospholipid Transfer Proteins/genetics [MeSH], Bone Resorption/genetics [MeSH], Phospholipid Transfer Proteins/metabolism [MeSH], 631/443/63, RANK Ligand/metabolism [MeSH], article, Bone Resorption/metabolism [MeSH], RANK Ligand, Medizin, Osteoclasts, Cell Differentiation, Phosphatidylserines, Cell Fusion, Mice, Inbred C57BL, Mice, 03 medical and health sciences, QP1-981, Animals, Biology (General), Phospholipid Transfer Proteins, Bone Resorption
Beschreibung: 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.
Publikationsart: Article
Other literature type
Sprache: English
ISSN: 2095-6231
DOI: 10.1038/s41413-024-00338-4
Zugangs-URL: https://pubmed.ncbi.nlm.nih.gov/38987568
https://doaj.org/article/a3409e48ebd5446880ba7bab830dfe79
https://repository.publisso.de/resource/frl:6491814
https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&origin=inward&scp=85198069876
https://www.ncbi.nlm.nih.gov/pubmed/38987568
https://doi.org/10.1038/s41413-024-00338-4
Rights: CC BY
Dokumentencode: edsair.doi.dedup.....c794a19d18c9b6e9eeee50c41bd1a1b1
Datenbank: OpenAIRE
Beschreibung
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.
ISSN:20956231
DOI:10.1038/s41413-024-00338-4