The natural product salicin alleviates osteoarthritis progression by binding to IRE1 alpha and inhibiting endoplasmic reticulum stress through the IRE1 alpha-I kappa B alpha-p65 signaling pathway

作者全名："Zhu, Zhenglin; Gao, Shengqiang; Chen, Cheng; Xu, Wei; Xiao, Pengcheng; Chen, Zhiyu; Du, Chengcheng; Chen, Bowen; Gao, Yan; Wang, Chunli; Liao, Junyi; Huang, Wei"

作者地址："[Zhu, Zhenglin; Gao, Shengqiang; Chen, Cheng; Xu, Wei; Xiao, Pengcheng; Chen, Zhiyu; Du, Chengcheng; Chen, Bowen; Liao, Junyi; Huang, Wei] Chongqing Med Univ, Dept Orthopaed Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Zhu, Zhenglin; Gao, Shengqiang; Xiao, Pengcheng; Du, Chengcheng; Chen, Bowen; Liao, Junyi; Huang, Wei] Chongqing Med Univ, Orthopaed Res Lab, Chongqing 400016, Peoples R China; [Gao, Yan; Wang, Chunli] Chongqing Univ, Coll Bioengn, Key Lab Biorheol Sci & Technol, Minist Educ,Natl Innovat & Attracting Talents 111, Chongqing 400030, Peoples R China"

通信作者："Liao, JY; Huang, W (通讯作者)，Chongqing Med Univ, Dept Orthopaed Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China.; Liao, JY; Huang, W (通讯作者)，Chongqing Med Univ, Orthopaed Res Lab, Chongqing 400016, Peoples R China."

来源：EXPERIMENTAL AND MOLECULAR MEDICINE

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000881659600001

JCR分区：Q1

影响因子：12.8

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：　

摘要："Despite the high prevalence of osteoarthritis (OA) in older populations, disease-modifying OA drugs (DMOADs) are still lacking. This study was performed to investigate the effects and mechanisms of the small molecular drug salicin (SA) on OA progression. Primary rat chondrocytes were stimulated with TNF-alpha and treated with or without SA. Inflammatory factors, cartilage matrix degeneration markers, and cell proliferation and apoptosis markers were detected at the mRNA and protein levels. Cell proliferation and apoptosis were evaluated by EdU assays or flow cytometric analysis. RNA sequencing, molecular docking and drug affinity-responsive target stability analyses were used to clarify the mechanisms. The rat OA model was used to evaluate the effect of intra-articular injection of SA on OA progression. We found that SA rescued TNF-alpha-induced degeneration of the cartilage matrix, inhibition of chondrocyte proliferation, and promotion of chondrocyte apoptosis. Mechanistically, SA directly binds to IRE1 alpha and occupies the IRE1 alpha phosphorylation site, preventing IRE1 alpha phosphorylation and regulating IRE1 alpha-mediated endoplasmic reticulum (ER) stress by IRE1 alpha-I kappa B alpha-p65 signaling. Finally, intra-articular injection of SA-loaded lactic-co-glycolic acid (PLGA) ameliorated OA progression by inhibiting IRE1 alpha-mediated ER stress in the OA model. In conclusion, SA alleviates OA by directly binding to the ER stress regulator IRE1 alpha and inhibits IRE1 alpha-mediated ER stress via IRE1 alpha-I kappa B alpha-p65 signaling. Topical use of the small molecular drug SA shows potential to modify OA progression. Osteoarthritis: Natural bark extract could limit disease progression Salicin, a small molecule extracted from willow bark, could provide a safe, effective injectable treatment for osteoarthritis, particularly in the early stages of the disease. Osteoarthritis is driven by stress in the intracellular endoplasmic reticulum (ER), which results in chronic inflammation and death of chondrocytes, the cells involved in cartilage formation. Salicin, which is metabolized into salicylic acid after oral ingestion, already forms the basis of aspirin and other anti-inflammatory pain relievers, but the exact mechanisms of its action in osteoarthritis are unclear. In experiments on cell cultures and rats, Junyi Liao, Wei Huang and co-workers at Chongqing Medical University, Chongqing, China, showed how salicin binds directly to a protein involved in promoting ER stress, blocking its activity. This in turn prevented the degeneration of the cartilage matrix and boosted levels of healthy chondrocytes."

基金机构："Key Laboratory of Biorheological Science and Technology, College of Bioengineering, Chongqing University; National Natural Science Foundation of China (NSFC) [81972069, 82002312]; Innovation Project from Chongqing Municipal Education Commission [CYB21169]; Science and Technology Research Program of Chongqing Education Commission [KJQN202100431, KJZD-M202100401]; Cultivating Program and Candidate of Tip-Top Talent of The First Affiliated Hospital of Chongqing Medical University [2018PYJJ-11, BJRC2021-04]; Cultivating Program of Postdoctoral Research of The First Affiliated Hospital of Chongqing Medical University [CYYY-BSHPYXM-202202]; Chongqing Medical University"

基金资助正文："We are grateful for the support of the Key Laboratory of Biorheological Science and Technology, College of Bioengineering, Chongqing University. The authors would like to thank Dr. Tingting Peng from the Chongqing BI Academy for technical and scientific support. The authors are also grateful to T.-C. He and Annie Wang of The University of Chicago Medical Center for critical reading of the manuscript. The reported work was supported by the National Natural Science Foundation of China (NSFC) (#81972069 and #82002312). This project was also supported by the Innovation Project from Chongqing Municipal Education Commission (#CYB21169), the Science and Technology Research Program of Chongqing Education Commission (#KJQN202100431 and #KJZD-M202100401), the Cultivating Program and Candidate of Tip-Top Talent of The First Affiliated Hospital of Chongqing Medical University (#2018PYJJ-11 and # BJRC2021-04), and the Cultivating Program of Postdoctoral Research of The First Affiliated Hospital of Chongqing Medical University (CYYY-BSHPYXM-202202). J.Y. was supported by a postdoctoral fellowship from Chongqing Medical University. Funding sources were not involved in designing the study; in collecting, analyzing and interpreting data; in writing the report; or in the decision to submit the paper for publication."