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

• Published in: Nature communications Vol. 14; no. 1; p. 616
• Main Authors: Whitlock, Jarred M., Leikina, Evgenia, Melikov, Kamran, De Castro, Luis Fernandez, Mattijssen, Sandy, Maraia, Richard J., Collins, Michael T., Chernomordik, Leonid V.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 631/443/63; 631/45; 631/80; Bone Resorption - metabolism; Cell Differentiation; Cell Fusion; Cell Membrane - metabolism; Cell surface; Fibrous dysplasia; Humanities and Social Sciences; Humans; La protein; Low molecular weights; Membrane Proteins - metabolism; Molecular weight; Monocytes; multidisciplinary; Osteoclastogenesis; Osteoclasts; Osteoclasts - metabolism; Osteogenesis; Osteoprogenitor cells; Phosphatidylserine; Proteins; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Therapeutic applications; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36168-x

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.