Strawberry notch homologue 2 regulates osteoclast fusion by enhancing the expression of DC-STAMP

• Published in: The Journal of experimental medicine Vol. 210; no. 10; pp. 1947 - 1960
• Main Authors: Maruyama, Kenta, Uematsu, Satoshi, Kondo, Takeshi, Takeuchi, Osamu, Martino, Mikaël M, Kawasaki, Takumi, Akira, Shizuo
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 23.09.2013
• Subjects: Animals; Bone and Bones - metabolism; Bone and Bones - pathology; Cell Differentiation - genetics; Enzyme Activation - genetics; Female; Fragaria; Gene Expression Regulation; Giant Cells; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; NF-kappa B - metabolism; Osteoblasts - cytology; Osteoblasts - metabolism; Osteoclasts - cytology; Osteoclasts - metabolism; Osteogenesis - genetics; Phenotype; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction; Toll-Like Receptors - metabolism
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20130512

Osteoclasts are multinucleated cells formed by fusion of mononuclear precursors in response to receptor activator of nuclear factor κB (NF-κB) ligand (RANKL). We found that RANKL induced expression of the DExD/H helicase family corepressor strawberry notch homologue 2 (Sbno2). Previous in vitro studies showed that Sbno2 is induced by IL-10 and is involved in NF-κB repression. However, the role of Sbno2 in vivo and its pleiotropic functions are unknown. Sbno2 gene targeting resulted in normal NF-κB activation by TLR ligands. However, Sbno2-deficient mice exhibited increased bone mass due to impaired osteoclast fusion. Expression of dendritic cell-specific transmembrane protein (DC-STAMP), a critical player in osteoclast fusion, was significantly attenuated, and cell fusion of Sbno2-deficient osteoclasts was rescued by DC-STAMP. Sbno2 directly bound to T cell acute lymphocytic leukemia 1 (Tal1) and attenuated its inhibition of DC-STAMP expression, leading to activation of the DC-STAMP promoter by microphthalmia-associated transcription factor (MITF). Thus, Sbno2 plays a pivotal role in bone homeostasis in vivo by fine-tuning osteoclast fusion.