Cell Surface-Bound La Protein Regulates The Cell Fusion Stage Of Osteoclastogenesis

Multinucleated osteoclasts, essential for skeletal remodeling in health and diseases, are formed by fusion of osteoclast precursors with each fusion event raising their bone-resorbing activity. Here we report that nuclear RNA chaperone, La protein moonlights as an osteoclast fusion regulator. Monocyte-to-osteoclast differentiation starts with a drastic decrease in La levels. Then La reappears as a proteasecleaved species at the cell surface where it promotes fusion by mechanisms independent of La-RNA interactions. Appearance-and-disappearance of cell-surface La act as an on-and-off switch of the fusion activity with fusion slowing down when surface La is replaced in mature osteoclasts by full-length nuclear La. Inhibiting 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. One-Sentence Summary A nuclear RNA chaperon moves to the surface of osteoclasts to control their formation and function in bone metabolism.