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Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis

Author

Listed:
  • Jarred M. Whitlock

    (Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health)

  • Evgenia Leikina

    (Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health)

  • Kamran Melikov

    (Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health)

  • Luis Fernandez Castro

    (National Institute of Dental and Craniofacial Research, National Institutes of Health)

  • Sandy Mattijssen

    (Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health)

  • Richard J. Maraia

    (Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health)

  • Michael T. Collins

    (National Institute of Dental and Craniofacial Research, National Institutes of Health)

  • Leonid V. Chernomordik

    (Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health)

Abstract

Multinucleated osteoclasts, essential for skeletal remodeling in health and disease, are formed by the fusion of osteoclast precursors, where each fusion event raises their bone-resorbing activity. Here we show that the nuclear RNA chaperone, La protein has an additional function as an osteoclast fusion regulator. Monocyte-to-osteoclast differentiation starts with a drastic decrease in La levels. As fusion begins, La reappears as a low molecular weight species at the osteoclast surface, where it promotes fusion. La’s role in promoting osteoclast fusion is independent of canonical La-RNA interactions and involves direct interactions between La and Annexin A5, which anchors La to transiently exposed phosphatidylserine at the surface of fusing osteoclasts. Disappearance of cell-surface La, and the return of full length La to the nuclei of mature, multinucleated osteoclasts, acts as an off switch of their fusion activity. Targeting surface La in a novel explant model of fibrous dysplasia inhibits excessive osteoclast formation characteristic of this disease, highlighting La’s potential as a therapeutic target.

Suggested Citation

  • Jarred M. Whitlock & Evgenia Leikina & Kamran Melikov & Luis Fernandez Castro & Sandy Mattijssen & Richard J. Maraia & Michael T. Collins & Leonid V. Chernomordik, 2023. "Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36168-x
    DOI: 10.1038/s41467-023-36168-x
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    1. Yuki Ikebuchi & Shigeki Aoki & Masashi Honma & Madoka Hayashi & Yasutaka Sugamori & Masud Khan & Yoshiaki Kariya & Genki Kato & Yasuhiko Tabata & Josef M. Penninger & Nobuyuki Udagawa & Kazuhiro Aoki , 2018. "Coupling of bone resorption and formation by RANKL reverse signalling," Nature, Nature, vol. 561(7722), pages 195-200, September.
    2. Gonen Golani & Evgenia Leikina & Kamran Melikov & Jarred M. Whitlock & Dilani G. Gamage & Gracia Luoma-Overstreet & Douglas P. Millay & Michael M. Kozlov & Leonid V. Chernomordik, 2021. "Myomerger promotes fusion pore by elastic coupling between proximal membrane leaflets and hemifusion diaphragm," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    3. Christian E. Jacome-Galarza & Gulce I. Percin & James T. Muller & Elvira Mass & Tomi Lazarov & Jiri Eitler & Martina Rauner & Vijay K. Yadav & Lucile Crozet & Mathieu Bohm & Pierre-Louis Loyher & Gera, 2019. "Developmental origin, functional maintenance and genetic rescue of osteoclasts," Nature, Nature, vol. 568(7753), pages 541-545, April.
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