East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai, China.
Nat Med. 2016 May;22(5):539-46. doi: 10.1038/nm.4076. Epub 2016 Apr 11.
Tumor necrosis factor (TNF) superfamily member 11 (TNFSF11, also known as RANKL) regulates multiple physiological or pathological functions, including osteoclast differentiation and osteoporosis. TNFRSF11A (also called RANK) is considered to be the sole receptor for RANKL. Herein we report that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL. LGR4 competes with RANK to bind RANKL and suppresses canonical RANK signaling during osteoclast differentiation. RANKL binding to LGR4 activates the Gαq and GSK3-β signaling pathway, an action that suppresses the expression and activity of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATC1) during osteoclastogenesis. Both whole-body (Lgr4(-/-)) and monocyte conditional knockout mice of Lgr4 (Lgr4 CKO) exhibit osteoclast hyperactivation (including elevation of osteoclast number, surface area, and size) and increased bone erosion. The soluble LGR4 extracellular domain (ECD) binds RANKL and inhibits osteoclast differentiation in vivo. Moreover, LGR4-ECD therapeutically abrogated RANKL-induced bone loss in three mouse models of osteoporosis. Therefore, LGR4 acts as a second RANKL receptor that negatively regulates osteoclast differentiation and bone resorption.
肿瘤坏死因子（TNF）超家族成员 11（TNFSF11，也称为 RANKL）调节多种生理或病理功能，包括破骨细胞分化和骨质疏松症。TNFRSF11A（也称为 RANK）被认为是 RANKL 的唯一受体。在此，我们报告富含亮氨酸重复的 G 蛋白偶联受体 4（LGR4，也称为 GPR48）是 RANKL 的另一个受体。LGR4 与 RANK 竞争结合 RANKL，并在破骨细胞分化过程中抑制经典的 RANK 信号。RANKL 与 LGR4 的结合激活 Gαq 和 GSK3-β 信号通路，该作用抑制核因子活化 T 细胞细胞质、钙调神经磷酸酶依赖性 1（NFATC1）在破骨细胞生成过程中的表达和活性。全身性（Lgr4(-/-)）和单核细胞条件性敲除 Lgr4（Lgr4 CKO）的小鼠均表现出破骨细胞过度激活（包括破骨细胞数量、表面积和大小的增加）和骨侵蚀增加。可溶性 LGR4 细胞外结构域（ECD）结合 RANKL 并在体内抑制破骨细胞分化。此外，LGR4-ECD 在三种骨质疏松症小鼠模型中治疗性地阻断了 RANKL 诱导的骨丢失。因此，LGR4 作为第二个 RANKL 受体，负调节破骨细胞分化和骨吸收。
