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

Weijia Sun, Shuai Guo, Yuheng Li, JianWei Li, Caizhi Liu, Yafei Chen, Xuzhao Wang, Yingjun Tan, Hua Tian, Cheng Wang, Ruikai Du, Guohui Zhong, Sai Shi, Biao Ma, Chang Qu, Jingxuan Fu, Xiaoyan Jin, Dingsheng Zhao, Yong Zhan, Shukuan Ling (), Hailong An () and Yingxian Li ()
Additional contact information
Weijia Sun: China Astronaut Research and Training Center
Shuai Guo: Hebei University of Technology
Yuheng Li: China Astronaut Research and Training Center
JianWei Li: China Astronaut Research and Training Center
Caizhi Liu: China Astronaut Research and Training Center
Yafei Chen: Hebei University of Technology
Xuzhao Wang: Hebei University of Technology
Yingjun Tan: China Astronaut Research and Training Center
Hua Tian: Peking University the Third Hospital
Cheng Wang: Peking University the Third Hospital
Ruikai Du: China Astronaut Research and Training Center
Guohui Zhong: China Astronaut Research and Training Center
Sai Shi: Hebei University of Technology
Biao Ma: Hebei University of Technology
Chang Qu: Hebei University of Technology
Jingxuan Fu: Hebei University of Technology
Xiaoyan Jin: China Astronaut Research and Training Center
Dingsheng Zhao: China Astronaut Research and Training Center
Yong Zhan: Hebei University of Technology
Shukuan Ling: China Astronaut Research and Training Center
Hailong An: Hebei University of Technology
Yingxian Li: China Astronaut Research and Training Center

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30625-9

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