PR11‐364P22.2/ATF3 protein interaction mediates IL‐1β‐induced catabolic effects in cartilage tissue and chondrocytes

Autor: Runzhi Liao, Xilei Li, Liang Chen, Qulian Guo, Yusheng Li, Yang Xucheng, Yang Junxiao
Rok vydání: 2021
Předmět:
Zdroj: Journal of Cellular and Molecular Medicine
ISSN: 1582-4934
1582-1838
DOI: 10.1111/jcmm.16561
Popis: Osteoarthritis (OA) is a degenerative joint disease which lacks effective medical treatment due to ill‐defined molecular mechanisms underlying the pathology. Inflammation is a key factor that induces and aggravates OA. Therefore, the current study aims to explore roles of the dysregulated long non‐coding RNAs in the pro‐inflammatory cytokine IL‐1β‐mediated catabolic effects in cartilage tissue and chondrocytes. We identified RP11‐364P22.2 as dysregulated in OA patient‐derived cartilage tissues and highly responsive to IL‐1β stimulus. RNA pull‐down coupled with mass spectrometry demonstrated that RP11‐364P22.2 physically binds to activating transcription factor 3 (ATF3) and thus increases the protein stability and facilitates its nuclear translocation. Loss‐ and gain‐of‐function assays indicated that the interaction between RP11‐364P22.2 and ATF3 is indispensable for the detrimental effects of IL‐1β including growth inhibition, apoptosis induction as well as degradation of the key chondrocyte structural proteins of type II collage and Aggrecan and synthesis of the extracellular matrix‐degrading enzyme MMP13 in chondrocytes. In vivo, depletion of the RP11‐364P22.2 effector ATF3 drastically prevented OA development in the rats with surgical destabilization of the medial meniscus (DMM). These results highlight the important roles of lncRNAs in the pathogenesis of OA and indicate the RP11‐364P22.2/ATF3 regulatory axis as a potential therapeutic target of inflammation‐induced OA.
Databáze: OpenAIRE
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