Caspase-8 promotes scramblase-mediated phosphatidylserine exposure and fusion of osteoclast precursors.
Journal
Bone research
ISSN: 2095-4700
Titre abrégé: Bone Res
Pays: China
ID NLM: 101608652
Informations de publication
Date de publication:
11 Jul 2024
11 Jul 2024
Historique:
received:
20
11
2022
accepted:
14
04
2024
revised:
10
04
2024
medline:
11
7
2024
pubmed:
11
7
2024
entrez:
10
7
2024
Statut:
epublish
Résumé
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. Proposed model of osteoclast fusion regulated by caspase-8 activation and PS exposure. RANK/RANK-L interaction. Activation of procaspase-8 into caspase-8. Caspase-8 activates caspase-3. Active capase-3 cleaves Xkr8. Local PS exposure is induced. Exposed PS is recognized by the fusion partner. FUSION. PS is re-internalized.
Identifiants
pubmed: 38987568
doi: 10.1038/s41413-024-00338-4
pii: 10.1038/s41413-024-00338-4
doi:
Substances chimiques
Caspase 8
EC 3.4.22.-
Phosphatidylserines
0
Phospholipid Transfer Proteins
0
RANK Ligand
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
40Subventions
Organisme : RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)
ID : (BB/T009543/1
Organisme : Wellcome Trust (Wellcome)
ID : 107964/Z/15/Z
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SCHE 2062/1-1
Informations de copyright
© 2024. The Author(s).
Références
Zaidi, M. Skeletal remodeling in health and disease. Nat. Med. 13, 791–801 (2007).
doi: 10.1038/nm1593
pubmed: 17618270
Jacome-Galarza, C. E. et al. Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature 568, 541–545 (2019).
doi: 10.1038/s41586-019-1105-7
pubmed: 30971820
pmcid: 6910203
Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).
doi: 10.1038/16852
pubmed: 9950424
Wada, T., Nakashima, T., Hiroshi, N. & Penninger, J. M. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol. Med. 12, 17–25 (2006).
doi: 10.1016/j.molmed.2005.11.007
pubmed: 16356770
Takayanagi, H. et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell 3, 889–901 (2002).
doi: 10.1016/S1534-5807(02)00369-6
pubmed: 12479813
Witwicka, H. et al. Studies of OC-STAMP in osteoclast fusion: a new knockout mouse model, rescue of cell fusion, and transmembrane topology. PLoS One 10, e0128275 (2015).
doi: 10.1371/journal.pone.0128275
pubmed: 26042409
pmcid: 4456411
Miyamoto, H. et al. Osteoclast stimulatory transmembrane protein and dendritic cell-specific transmembrane protein cooperatively modulate cell-cell fusion to form osteoclasts and foreign body giant cells. J. Bone Min. Res. 27, 1289–1297 (2012).
doi: 10.1002/jbmr.1575
Segawa, K. & Nagata, S. An apoptotic ‘Eat Me’ signal: phosphatidylserine exposure. Trends Cell Biol. 25, 639–650 (2015).
doi: 10.1016/j.tcb.2015.08.003
pubmed: 26437594
Ravichandran, K. S. & Lorenz, U. Engulfment of apoptotic cells: signals for a good meal. Nat. Rev. Immunol. 7, 964–974 (2007).
doi: 10.1038/nri2214
pubmed: 18037898
Wu, Y., Tibrewal, N. & Birge, R. B. Phosphatidylserine recognition by phagocytes: a view to a kill. Trends Cell Biol. 16, 189–197 (2006).
doi: 10.1016/j.tcb.2006.02.003
pubmed: 16529932
Nagata, S., Suzuki, J., Segawa, K. & Fujii, T. Exposure of phosphatidylserine on the cell surface. Cell Death Differ. 23, 952–961 (2016).
doi: 10.1038/cdd.2016.7
pubmed: 26891692
pmcid: 4987739
Nagata, S., Sakuragi, T. & Segawa, K. Flippase and scramblase for phosphatidylserine exposure. Curr. Opin. Immunol. 62, 31–38 (2020).
doi: 10.1016/j.coi.2019.11.009
pubmed: 31837595
Rosas, M. et al. Hoxb8 conditionally immortalised macrophage lines model inflammatory monocytic cells with important similarity to dendritic cells. Eur. J. Immunol. 41, 356–365 (2011).
doi: 10.1002/eji.201040962
pubmed: 21268006
Koizumi, K. et al. Role of CX3CL1/fractalkine in osteoclast differentiation and bone resorption. J. Immunol. 183, 7825–7831 (2009).
doi: 10.4049/jimmunol.0803627
pubmed: 19923448
Li, J. & Yuan, J. Caspases in apoptosis and beyond. Oncogene 27, 6194–6206 (2008).
doi: 10.1038/onc.2008.297
pubmed: 18931687
Mukherjee, A. & Williams, D. W. More alive than dead: non-apoptotic roles for caspases in neuronal development, plasticity and disease. Cell Death Differ. 24, 1411–1421 (2017).
doi: 10.1038/cdd.2017.64
pubmed: 28644437
pmcid: 5520460
Günther, C. et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477, 335–339 (2011).
doi: 10.1038/nature10400
pubmed: 21921917
pmcid: 3373730
Szymczyk, K. H., Freeman, T. A., Adams, C. S., Srinivas, V. & Steinbeck, M. J. Active caspase-3 is required for osteoclast differentiation. J. Cell Physiol. 209, 836–844 (2006).
doi: 10.1002/jcp.20770
pubmed: 16972256
Svandova, E., Vesela, B., Tucker, A. S. & Matalova, E. Activation of pro-apoptotic caspases in non-apoptotic cells during odontogenesis and related osteogenesis. Front. Physiol. 9, 174 (2018).
Kearney, C. J. et al. Inhibitor of apoptosis proteins (IAPs) and their antagonists regulate spontaneous and tumor necrosis factor (TNF)-induced proinflammatory cytokine and chemokine production. J. Biol. Chem. 288, 4878–4890 (2013).
doi: 10.1074/jbc.M112.422410
pubmed: 23275336
Klöditz, K. & Fadeel, B. Three cell deaths and a funeral: macrophage clearance of cells undergoing distinct modes of cell death. Cell Death Discov. 5, 65 (2019).
doi: 10.1038/s41420-019-0146-x
pubmed: 30774993
pmcid: 6368547
Fadok, V. A., Bratton, D. L. & Henson, P. M. Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences. J. Clin. Invest. 108, 957–962 (2001).
doi: 10.1172/JCI200114122
pubmed: 11581295
pmcid: 200959
Segawa, K. et al. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344, 1164–1168 (2014).
doi: 10.1126/science.1252809
pubmed: 24904167
Kang, J. H. et al. Dual role of phosphatidylserine and its receptors in osteoclastogenesis. Cell Death Dis. 11, 497 (2020).
doi: 10.1038/s41419-020-2712-9
pubmed: 32612123
pmcid: 7330034
Verma, S. K. et al. Cell-surface phosphatidylserine regulates osteoclast precursor fusion. J. Biol. Chem. 293, 254–270 (2018).
doi: 10.1074/jbc.M117.809681
pubmed: 29101233
Ravichandran, K. S. Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. J. Exp. Med. 207, 1807–1817 (2010).
doi: 10.1084/jem.20101157
pubmed: 20805564
pmcid: 2931173
Tsuchiya, M. et al. Cell surface flip-flop of phosphatidylserine is critical for PIEZO1-mediated myotube formation. Nat. Commun. 9, 2049 (2018).
doi: 10.1038/s41467-018-04436-w
pubmed: 29799007
pmcid: 5967302
Kim, G. W., Park, S. Y. & Kim, I. S. Novel function of stabilin-2 in myoblast fusion: the recognition of extracellular phosphatidylserine as a “fuse-me” signal. BMB Rep. 49, 303–304 (2016).
doi: 10.5483/BMBRep.2016.49.6.078
pubmed: 27174501
pmcid: 5070716
Hochreiter-Hufford, A. E., Arandjelovic, S. & Ravichandran, K. S. Using phosphatidylserine exposure on apoptotic cells to stimulate myoblast fusion. Methods Mol. Biol. 1313, 141–148 (2015).
doi: 10.1007/978-1-4939-2703-6_10
pubmed: 25947662
pmcid: 4473771
Hochreiter-Hufford, A. E. et al. Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion. Nature 497, 263–267 (2013).
doi: 10.1038/nature12135
pubmed: 23615608
pmcid: 3773542