Progranulin deficiency associates with postmenopausal osteoporosis via increasing ubiquitination of estrogen receptorα  

作　　者：Guangfei Li Aifei Wang Wei Tang Wenyu Fu Qingyun Tian Jinlong Jian Michal Lata Aubryanna Hettinghouse Yuanjing Ding Jianlu Wei Xiangli Zhao Mingyong Wang Qirong Dong Chuanju Liu Youjia Xu 

机构地区：[1]Department of Orthopedics,Second Affiliated Hospital of Soochow University,Suzhou,Jiangsu 215004,China [2]Department of Orthopaedic Surgery,New York University Grossman School of Medicine,New York,NY 10003,USA [3]Osteoporosis Institute of Soochow University,Suzhou,Jiangsu 215004,China [4]Department of Pathogenic Biology,School of Basic Medical Sciences,Shandong University,Jinan,Shandong 250012,China [5]Department of Orthopaedics and Rehabilitation,Yale University School of Medicine,New Haven,CT 06510,USA [6]Department of Orthopaedic Surgery,Jinan Central Hospital Affiliated to Shandong First Medical University,Jinan,Shandong 250013,China [7]Department of Orthopaedic Surgery,Qilu Hospital of Shandong University,Jinan,Shandong 250012,China [8]Murui Biological Technology Co.,Ltd.,Suzhou Industrial Park,Suzhou,Jiangsu 215123,China [9]Department of Cell Biology,New York University Grossman School of Medicine,New York,NY 10016,USA

出　　处：《Genes & Diseases》2025年第1期312-326,共15页基因与疾病(英文)

基　　金：supported by the grants from China Scholarship Council(No.201505320002);the National Institutes of Health(No.R01AR062207,R01AR061484,R01AR076900,R01NS103931);Young Medical Talents Program of Jiangsu Province,China(No.QNRC2016878);National Key R&D Program of China(No.SQ2021YFC2501702);Natural Science Foundation of China(No.82072474);Clinical Medicine Technology Project of Jiangsu Province,China(No.BE2019661).

摘　　要：Estrogen deficiency is considered the most important cause of postmenopausal osteoporosis.However,the underlying mechanism is still not completely understood.In this study,progranulin(PGRN)was isolated as a key regulator of bone mineral density in postmenopausal women through high throughput proteomics screening.In addition,PGRN-deficient mice exhibited significantly lower bone mass than their littermates in an ovariectomy-induced osteoporosis model.Furthermore,estrogen-mediated inhibition of osteoclastogenesis and bone resorption as well as its protection against ovariectomy-induced bone loss largely depended on PGRN.Mechanistic studies revealed the existence of a positive feedback regulatory loop between PGRN and estrogen signaling.In addition,loss of PGRN led to the reduction of estrogen receptorα,the important estrogen receptor involved in estrogen regulation of osteoporosis,through enhancing its degradation via K48-linked ubiquitination.These findings not only provide a previously unrecognized interplay between PGRN and estrogen signaling in regulating osteoclastogenesis and osteoporosis but may also present a new therapeutic approach for the prevention and treatment of postmenopausal osteoporosis by targeting PGRN/estrogen receptorα.

关 键 词：Estrogen receptorα OSTEOCLASTOGENESIS Postmenopausal osteoporosis Progranulin UBIQUITINATION 

分 类 号：R681[医药卫生—骨科学]