Mechanical protein polycystin-1 directly regulates osteoclastogenesis and bone resorption

Mei Huang ¹Jingxuan Zhou ¹Xiaoxiao Li ²Ran Liu ¹Yangzi Jiang ³Kaixuan Chen ¹Yurui Jiao ¹Xin Yin ¹Ling Liu ¹Yuchen Sun ¹Weishan Wang ⁴Ye Xiao ¹Tian Su ¹Qi Guo ¹Yan Huang ¹Mi Yang ¹Jie Wei ⁵L.Darryl Quarles ⁶Zhousheng Xiao ⁶Chao Zeng ⁷Xianghang Luo ⁸Guanghua Lei ⁷Changjun Li⁹

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作者信息

1. Department of Endocrinology,Endocrinology Research Center,Xiangya Hospital,Central South University,Changsha 410008,China
2. 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
3. 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
4. Department of Orthopaedics,The First Affiliated Hospital of Shihezi University,Shihezi 832061,China
5. 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;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
6. Department of Medicine,University of Tennessee Health Science Center,Memphis 38163,USA
7. 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;Department of Orthopaedics,Xiangya Hospital,Central South University,Changsha 410008,China;National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha 410008,China
8. Department of Endocrinology,Endocrinology Research Center,Xiangya Hospital,Central South University,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;National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha 410008,China
9. Department of Endocrinology,Endocrinology Research Center,Xiangya Hospital,Central South University,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;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
折叠

Abstract

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 osteo-clast 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 dis-ease,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.

Key words

Polycystin1/Osteoclastogenesis/Bone resorption/Mechanical stress

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基金项目

National Key Research and Development Program of China(2019YFA0111900)

National Key Research and Development Program of China(2022YFC3601900)

National Key Research and Development Program of China(2022YFC2505500)

National Natural Science Foundation of China(82261160397)

National Natural Science Foundation of China(82272560)

National Natural Science Foundation of China(81922017)

National Natural Science Foundation of China(92149306)

National Natural Science Foundation of China(82120108009)

NSFC/RGC Joint Research Scheme()

Research Grants Council(UGC)of the Hong Kong Special Administrative Region()

National Natural Science Foundation of China(N_CUHK483/22)

Center for Neuromusculoskeletal Restorative Medicine by Innovation and Technology Commission(ITC)of Hong Kong SAR,China(CNRM()

National Institutes of Health(R61-AR073518)

National Institutes of Health(R01-AR071930)

Key Research and Development Program of Hunan Province(2022SK2023)

Science and Technology Innovation Program of Hunan Province(2023RC1027)

Science and Technology Innovation Program of Hunan Province(2022RC1009)

Science and Technology Innovation Program of Hunan Province(2022RC3075)

Hunan Provincial Science and Technology Department(2023JJ30896)

出版年

2024

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

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