AUTHOR=Gao Yanchun , Wei Haifeng , Peng Xiaoyuan , Wang Chenchen , Zhu Hongyi , Yin Junhui 

TITLE=ER stress-induced YAP upregulation leads to chondrocyte phenotype loss in age-related osteoarthritis

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1476255

DOI=10.3389/fphar.2024.1476255

ISSN=1663-9812

ABSTRACT=Background: Osteoarthritis (OA) is a common degenerative joint disease, leading to pain and restricted mobility. Age-related endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of OA, but the underlying mechanisms remain unclear.This study aims to explore the relationship between age-related ER stress, YAP overexpression, and chondrocyte phenotype loss in the development of OA. Methods:Cartilage samples were collected from patients undergoing amputation, and age-related ER stress markers and YAP expression were assessed using immunohistochemical staining and qPCR. Transgenic mice with cartilage-specific YAP overexpression (YAP OE ) were created, and Pamrevlumab was administered to evaluate its therapeutic effects. Results: Higher expression of ER stress markers and YAP were showed in aged tissues compared to younger tissues. YAP overexpression led to decreased levels of cartilage phenotype markers and increased osteogenesis-related proteins. In vivo, YAP OE mice exhibited OA-like cartilage degeneration, which was mitigated by Pamrevlumab treatment. Conclusions: Age-related ER stress induces YAP overexpression, contributing to OA pathogenesis. Pamrevlumab effectively prevents this phenotype loss in YAP OE mice, suggesting its potential as a therapeutic agent for OA. These findings provide new insights into the molecular mechanisms of OA and highlight the importance of targeting the ER stress-YAP-CTGF signaling pathway in OA treatment and prevention.