Kim Hyunsoo, Takegahara Noriko, Walsh Matthew C, Middleton Sarah A, Yu Jiyeon, Shirakawa Jumpei, Ueda Jun, Fujihara Yoshitaka, Ikawa Masahito, Ishii Masaru, Kim Junhyong, Choi Yongwon
1Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 USA.
2Department of Biology, Department of Computer and Information Science, School of Arts and Sciences, Program in Single Cell Biology, University of Pennsylvania, Philadelphia, PA 19104 USA.
Bone Res. 2020 Feb 10;8:5. doi: 10.1038/s41413-019-0080-9. eCollection 2020.
Osteoclasts are multinucleated, giant cells derived from myeloid progenitors. While receptor activator of NF-κB ligand (RANKL) stimulation is the primary driver of osteoclast differentiation, additional signaling further contributes to osteoclast maturation. Here, we demonstrate that immunoglobulin superfamily member 11 (IgSF11), whose expression increases during osteoclast differentiation, regulates osteoclast differentiation through interaction with postsynaptic density protein 95 (PSD-95), a scaffold protein with multiple protein interaction domains. IgSF11 deficiency in vivo results in impaired osteoclast differentiation and bone resorption but no observed defect in bone formation. Consequently, IgSF11-deficient mice exhibit increased bone mass. Using in vitro osteoclast culture systems, we show that IgSF11 functions through homophilic interactions. Additionally, we demonstrate that impaired osteoclast differentiation in IgSF11-deficient cells is rescued by full-length IgSF11 and that the IgSF11-PSD-95 interaction requires the 75 C-terminal amino acids of IgSF11. Our findings reveal a critical role for IgSF11 during osteoclast differentiation and suggest a role for IgSF11 in a receptor- and signal transduction molecule-containing protein complex.
破骨细胞是源自髓系祖细胞的多核巨细胞。虽然核因子κB受体活化因子配体（RANKL）刺激是破骨细胞分化的主要驱动因素，但其他信号传导进一步促进破骨细胞成熟。在此，我们证明免疫球蛋白超家族成员11（IgSF11）在破骨细胞分化过程中表达增加，它通过与突触后密度蛋白95（PSD-95）相互作用来调节破骨细胞分化，PSD-95是一种具有多个蛋白质相互作用结构域的支架蛋白。体内IgSF11缺乏会导致破骨细胞分化和骨吸收受损，但未观察到骨形成缺陷。因此，IgSF11缺陷小鼠的骨量增加。使用体外破骨细胞培养系统，我们表明IgSF11通过同型相互作用发挥作用。此外，我们证明全长IgSF11可挽救IgSF11缺陷细胞中受损的破骨细胞分化，并且IgSF11与PSD-95的相互作用需要IgSF11的75个C末端氨基酸。我们的研究结果揭示了IgSF11在破骨细胞分化过程中的关键作用，并表明IgSF11在包含受体和信号转导分子的蛋白质复合物中发挥作用。
