Lefty2 prevents RANKL-induced bone loss by inhibiting osteoclast differentiation.

Left-right determination factor 2 (Lefty2) is a transforming growth factor-β (TGF-β) receptor ligand that is critical for organ asymmetry and cell proliferation. More broadly, the TGF-β superfamily plays indispensable roles in development and gene regulation, and TGF-β family ligands are instrumental in osteoclast differentiation and bone resorption. In the present study, we show that Lefty2 dramatically inhibits receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclast differentiation. We found that this effect was associated with inhibition of early intracellular signaling pathways activated by RANKL, which are important for osteoclast differentiation. Furthermore, administration of exogenous Lefty2 prevented RANKL-induced bone loss in mice. Interestingly, transgenic mice expressing Lefty2 controlled by the Mx-1 promoter did not show a distinct bone phenotype, even though transgenic mouse-derived bone marrow macrophages exhibited reduced osteoclast formation compared to controls in vitro.