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

Jarred M WhitlockEvgenia LeikinaKamran MelikovLuis Fernandez De CastroSandy MattijssenRichard J MaraiaMichael T CollinsLeonid V Chernomordik
Published in: Nature communications (2023)
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.
Keyphrases
  • bone loss
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  • physical activity
  • binding protein
  • cell therapy
  • protein protein
  • amino acid
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