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- Title
Cell surface-bound La protein regulates the cell fusion stage of osteoclastogenesis.
- Authors
Whitlock, Jarred M.; Leikina, Evgenia; Melikov, Kamran; De Castro, Luis Fernandez; Mattijssen, Sandy; Maraia, Richard J.; Collins, Michael T.; Chernomordik, Leonid V.
- 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. Bone maintenance in health and disease depends on bone-resorbing osteoclasts. Whitlock et al. demonstrate that an RNA chaperon -La protein- lives a second life as a key regulator of osteoclast size and function, suggesting a new therapeutic target.
- Subjects
CELL fusion; OSTEOCLASTOGENESIS; BONE health; MOLECULAR weights; ANNEXINS; PHOSPHATIDYLSERINES
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-36168-x