Anoctamin 1 controls bone resorption by coupling Cl− channel activation with RANKL-RANK signaling transduction

• Published in: Nature communications Vol. 13; no. 1; pp. 2899 - 15
• Main Authors: Sun, Weijia, Guo, Shuai, Li, Yuheng, Li, JianWei, Liu, Caizhi, Chen, Yafei, Wang, Xuzhao, Tan, Yingjun, Tian, Hua, Wang, Cheng, Du, Ruikai, Zhong, Guohui, Shi, Sai, Ma, Biao, Qu, Chang, Fu, Jingxuan, Jin, Xiaoyan, Zhao, Dingsheng, Zhan, Yong, Ling, Shukuan, An, Hailong, Li, Yingxian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.05.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/89; 14/19; 38/61; 631/337; 631/80/304; 631/80/86/1999; 64/110; 64/60; 9/74; Animals; Anoctamin-1 - metabolism; Biomedical materials; Bone loss; Bone mass; Bone resorption; Bone Resorption - metabolism; Calcium chloride; Channel gating; Chloride; Chloride channels (calcium-gated); Chloride ions; Coupling; Deletion; Female; Homeostasis; Humanities and Social Sciences; Humans; Ion channels; Mice; Mice, Inbred C57BL; multidisciplinary; NFATC Transcription Factors - metabolism; Osteoclasts - metabolism; Osteogenesis - genetics; Osteoporosis; Osteoporosis - metabolism; Ovariectomy; RANK Ligand - genetics; RANK Ligand - metabolism; Science; Science (multidisciplinary); Signal transduction; Signaling; Therapeutic targets; TRANCE protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-30625-9

Osteoclast over-activation leads to bone loss and chloride homeostasis is fundamental importance for osteoclast function. The calcium-activated chloride channel Anoctamin 1 (also known as TMEM16A) is an important chloride channel involved in many physiological processes. However, its role in osteoclast remains unresolved. Here, we identified the existence of Anoctamin 1 in osteoclast and show that its expression positively correlates with osteoclast activity. Osteoclast-specific Anoctamin 1 knockout mice exhibit increased bone mass and decreased bone resorption. Mechanistically, Anoctamin 1 deletion increases intracellular Cl − concentration, decreases H + secretion and reduces bone resorption. Notably, Anoctamin 1 physically interacts with RANK and this interaction is dependent upon Anoctamin 1 channel activity, jointly promoting RANKL-induced downstream signaling pathways. Anoctamin 1 protein levels are substantially increased in osteoporosis patients and this closely correlates with osteoclast activity. Finally, Anoctamin 1 deletion significantly alleviates ovariectomy induced osteoporosis. These results collectively establish Anoctamin 1 as an essential regulator in osteoclast function and suggest a potential therapeutic target for osteoporosis. Osteoclast over-activation leads to bone loss and chloride homeostasis is important for osteoclast function. Here, the authors show that Anoctamin 1 controls bone resorption by coupling Cl − channel activation with RANKL-RANK signaling transduction.