IRE1α protects against osteoarthritis by regulating progranulin-dependent XBP1 splicing and collagen homeostasis

作者全名："Liang, Li; Zhang, Fengmei; Feng, Naibo; Kuang, Biao; Fan, Mengtian; Chen, Cheng; Pan, Yiming; Zhou, Pengfei; Geng, Nana; Li, Xingyue; Xian, Menglin; Deng, Lin; Li, Xiaoli; Kuang, Liang; Luo, Fengtao; Tan, Qiaoyan; Xie, Yangli; Guo, Fengjin"

作者地址："[Liang, Li; Zhang, Fengmei; Feng, Naibo; Fan, Mengtian; Pan, Yiming; Geng, Nana; Li, Xingyue; Xian, Menglin; Deng, Lin; Li, Xiaoli; Guo, Fengjin] Chongqing Med Univ, Sch Basic Med Sci, Dept Cell Biol & Genet, Lab Dev Biol, Chongqing 400016, Peoples R China; [Zhang, Fengmei] Chongqing Med Univ, Lab Anim Ctr, Chongqing 400016, Peoples R China; [Kuang, Biao] Chongqing Med Univ, Affiliated Hosp 2, Dept Orthoped, Chongqing 400072, Peoples R China; [Chen, Cheng] Chongqing Med Univ, Affiliated Hosp 1, Dept Orthoped, Chongqing 400016, Peoples R China; [Zhou, Pengfei] Chongqing Med Univ, Coll Stomatol, Chongqing Key Lab Oral Dis & Biomed Sci, Chongqing 400016, Peoples R China; [Kuang, Liang; Luo, Fengtao; Tan, Qiaoyan; Xie, Yangli] Army Med Univ, Daping Hosp, Res Inst Surg, Ctr Bone Metab & Repair CBMR,Dept Wound Repair & R, Chongqing 400042, Peoples R China"

通信作者："Guo, FJ (通讯作者)，Chongqing Med Univ, Sch Basic Med Sci, Dept Cell Biol & Genet, Lab Dev Biol, Chongqing 400016, Peoples R China."

来源：EXPERIMENTAL AND MOLECULAR MEDICINE

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001094284300001

JCR分区：Q1

影响因子：9.5

年份：2023

卷号：　

期号：　

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结束页：　

文献类型：Article; Early Access

关键词：　

摘要："Osteoarthritis (OA) is a full-joint, multifactorial, degenerative and inflammatory disease that seriously affects the quality of life of patients due to its disabling and pain-causing properties. ER stress has been reported to be closely related to the progression of OA. The inositol-requiring enzyme 1 alpha/X-box-binding protein-1 spliced (IRE1 alpha/XBP1s) pathway, which is highly expressed in the chondrocytes of OA patients, promotes the degradation and refolding of abnormal proteins during ER stress and maintains the stability of the ER environment of chondrocytes, but its function and the underlying mechanisms of how it contributes to the progression of OA remain unclear. This study investigates the role of IRE1 alpha/ERN1 in OA. Specific deficiency of ERN1 in chondrocytes spontaneously resulted in OA-like cartilage destruction and accelerated OA progression in a surgically induced arthritis model. Local delivery of AdERN1 relieved degradation of the cartilage matrix and prevented OA development in an ACLT-mediated model. Mechanistically, progranulin (PGRN), an intracellular chaperone, binds to IRE1 alpha, promoting its phosphorylation and splicing of XBP1u to generate XBP1s. XBP1s protects articular cartilage through TNF-alpha/ERK1/2 signaling and further maintains collagen homeostasis by regulating type II collagen expression. The chondroprotective effect of IRE1 alpha/ERN1 is dependent on PGRN and XBP1s splicing. ERN1 deficiency accelerated cartilage degeneration in OA by reducing PGRN expression and XBP1s splicing, subsequently decreasing collagen II expression and triggering collagen structural abnormalities and an imbalance in collagen homeostasis. This study provides new insights into OA pathogenesis and the UPR and suggests that IRE1 alpha/ERN1 may serve as a potential target for the treatment of joint degenerative diseases, including OA. Researchers have discovered that the ERN1/IRE1 alpha plays a protective role in cartilage by regulating the PGRN-dependent XBP1 splicing and collagen homeostasis. The study found that cartilage-specific deficiency of ERN1 in mice led to spontaneous osteoarthritis development and more severe cartilage damage in a surgically induced arthritis model. Furthermore, the chondroprotective effect of IRE1 alpha was dependent on PGRN, an intracellular molecular chaperone that interacts with ERN1/IRE1 alpha. This research provides new insights into the role of IRE1 alpha in osteoarthritis progression and highlights its potential as a therapeutic target for degenerative joint diseases."

基金机构："We are particularly grateful to Professor Chuanju Liu of New York University and Professor Lin Chen of Daping Hospital of Army Medical University for their strong support and help with this project. This work was supported by the National Natural Science F [82272550, 81871769]; National Natural Science Foundation of China [2021M700632]; Postdoctoral Science Foundation of China [2020-379-46]; Special Postdoctoral Science Foundation of Chongqing"

基金资助正文："We are particularly grateful to Professor Chuanju Liu of New York University and Professor Lin Chen of Daping Hospital of Army Medical University for their strong support and help with this project. This work was supported by the National Natural Science Foundation of China (No. 82272550, No. 81871769), the Postdoctoral Science Foundation of China (No. 2021M700632), and the Special Postdoctoral Science Foundation of Chongqing (No. 2020-379-46). All experiments were completed on the experimental platform provided by the Core Facility of Development Biology of Basic Medical College (Chongqing Medical University)."