破骨细胞
骨吸收
骨重建
条件基因敲除
内分泌学
骨质疏松症
内科学
吸收
包装D1
化学
细胞生物学
医学
癌症研究
常染色体显性多囊肾病
生物
肾
表型
基因
受体
生物化学
作者
Mei Huang,Jing Zhou,Xiao Xiao Li,Ran Liu,Yangzi Jiang,Kai Xuan Chen,Yang Jiao,Xin Yin,Ling Liu,Yu Sun,Wei Shan Wang,Ye Xiao,Tian Su,Qi Guo,Yan Huang,Mi Yang,Jie Wei,L. Darryl Quarles,Zhou Xiao,Chao Zeng,Xiang Luo,Guang-hua Lei,Chang Jun Li
标识
DOI:10.1016/j.scib.2024.04.044
摘要
Mechanical loading is required for bone homeostasis, but the underlying mechanism is still unclear. Our previous studies revealed that the mechanical protein polycystin-1 (PC1, encoded by Pkd1) is critical for bone formation. However, the role of PC1 in bone resorption is unknown. Here, we found that PC1 directly regulates osteoclastogenesis and bone resorption. The conditional deletion of Pkd1 in the osteoclast lineage resulted in a reduced number of osteoclasts, decreased bone resorption, and increased bone mass. A cohort study of 32,500 patients further revealed that autosomal dominant polycystic kidney disease, which is mainly caused by loss-of-function mutation of the PKD1 gene, is associated with a lower risk of hip fracture than those with other chronic kidney diseases. Moreover, mice with osteoclast-specific knockout of Pkd1 showed complete resistance to unloading-induced bone loss. A mechanistic study revealed that PC1 facilitated TAZ nuclear translocation via the C-terminal tail-TAZ complex and that conditional deletion of Taz in the osteoclast lineage resulted in reduced osteoclastogenesis and increased bone mass. Pharmacological regulation of the PC1-TAZ axis alleviated unloading- and estrogen deficiency- induced bone loss. Thus, the PC1-TAZ axis may be a potential therapeutic target for osteoclast-related osteoporosis.
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