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 PC1directly 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 osteoclastspecific 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.
作者
黄梅
周静璇
李潇骁
刘冉
姜洋子
陈开璇
焦玉睿
尹欣
刘玲
孙宇晨
王维山
肖业
苏甜
郭奇
黄燕
杨觅
魏婕
L.Darryl Quarles
肖洲生
曾超
罗湘杭
雷光华
李长俊
Mei Huang;Jingxuan Zhou;Xiaoxiao Li;Ran Liu;Yangzi Jiang;Kaixuan Chen;Yurui Jiao;Xin Yin;Ling Liu;Yuchen Sun;Weishan Wang;Ye Xiao;Tian Su;Qi Guo;Yan Huang;Mi Yang;Jie Wei;L.Darryl Quarles;Zhousheng Xiao;Chao Zeng;Xianghang Luo;Guanghua Lei;Changjun Li(Department of Endocrinology,Endocrinology Research Center,Xiangya Hospital,Central South University,Changsha 410008,China;Hunan Key Laboratory of Joint Degeneration and Injury,Changsha 410008,China;Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment,Ministry of Education,Xiangya Hospital,Central South University,Changsha 410008,China;School of Biomedical Sciences,Institute for Tissue Engineering and Regenerative Medicine,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong 999077,China;Key Laboratory for Regenerative Medicine,Ministry of Education,School of Biomedical Sciences,Faculty of Medicine,The Chinese University of Hong Kong,Hong Kong 999077,China;Center for Neuromusculoskeletal Restorative Medicine(CNRM),The Chinese University of Hong Kong,Hong Kong 999077,China;Department of Orthopaedics,The First Affiliated Hospital of Shihezi University,Shihezi 832061,China;Department of Orthopaedics,Xiangya Hospital,Central South University,Changsha 410008,China;Department of Epidemiology and Health Statistics,Xiangya School of Public Health,Central South University,Changsha 410008,China;Department of Medicine,University of Tennessee Health Science Center,Memphis 38163,USA;National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha 410008,China;Laboratory Animal Center,Xiangya Hospital,Central South University,Changsha 410008,China)
基金
supported by the National Key Research and Development Program of China(2019YFA0111900,2022YFC3601900 and 2022YFC2505500)
the National Natural Science Foundation of China(82261160397,82272560,81922017,92149306 and 82120108009)
the NSFC/RGC Joint Research Scheme
the Research Grants Council(UGC)of the Hong Kong Special Administrative Region and the National Natural Science Foundation of China(N_CUHK483/22)
the Center for Neuromusculoskeletal Restorative Medicine by Innovation and Technology Commission(ITC)of Hong Kong SAR,China(CNRM at Inno HK),the National Institutes of Health(R61-AR073518 and R01-AR071930)
the Key Research and Development Program of Hunan Province(2022SK2023)
the Science and Technology Innovation Program of Hunan Province(2023RC1027,2022RC1009 and 2022RC3075)
the Hunan Provincial Science and Technology Department(2023JJ30896)。
