Receptor-interacting Protein Kinase 3 Promotes Osteoarthritis-related Changes by Upregulating Integrin Subunit Beta 3
10.13865/j.cnki.cjbmb.2021.02.1687
- Author:
Jin CHENG
1
;
Yan-Fang JIANG
1
;
Xiao-Ning DUAN
1
;
Xin FU
1
;
Ji-Ying ZHANG
1
;
Xiao-Qing HU
1
;
Ying-Fang AO
1
Author Information
1. Department of Sports Medicine, Peking University Third Hospital, Institute of Sports Medicine of Peking University, Beijing Key Laboratory of Sports Injuries
- Publication Type:Journal Article
- Keywords:
chondrocytes;
integrin beta 3(Itgb3);
necroptosis;
osteoarthritis (OA);
receptor-interacting protein kinase 3 (RIP3)
- From:
Chinese Journal of Biochemistry and Molecular Biology
2021;37(3):391-400
- CountryChina
- Language:Chinese
-
Abstract:
Osteoarthritis (OA) is the most common chronic disabling joint disease, and currently there is no effective treatment for the cause. Necroptosis plays a key role in many diseases, and receptor-interacting protein kinase 3 (RIP3) is a key regulator during necroptosis process. Studies have shown that the expression level of RIP3 was significantly upregulated in human and mouse OA degenerative cartilage tissues, suggesting the occurrence of necroptosis. However, the specific pathophysiological role of RIP3 in cartilage is still unclear. This study intends to sequence and analyze the transcriptome of chondrocytes before and after RIP3 overexpression, and explore the specific functional mechanism of RIP3 in OA pathogenesis. RNA sequencing results showed that overexpression of RIP3 induced upregulation of 244 genes and downregulation of 277 genes in chondrocytes. Sixteen candidate target genes were screened out by constructing gene co-expression network for further verification at mRNA level, and the results suggested that RIP3 had the most significant inductive effect on the expression of phosphoinositide-3kinase, regulatory subunit 5 (Pik3r5), integrin subunit beta 3 (Itgb3) and MYB proto-oncogene like 2 (Mybl2). Results from CCK-8 and lactate dehydrogenase activity analysis showed that silencing the expression of Itgb3 by siRNA significantly rescued chondrocyte viability decline and necroptosis induced by RIP3, and it also inhibited the upregulating effect of RIP3 on the expression of catabolism-related genes Mmp1, Mmp13 and Il6, as well as the downregulating effect of RIP3 on the expression of anabolism-related genes Acan, Col2a1 and Sox9. This study has demonstrated that RIP3 promotes chondrocyte necrosis and cartilage matrix metabolism disorders by upregulating the expression of Itgb3 in chondrocytes, and ultimately leads to cartilage degeneration. These findings provided potential novel targets for the clinical treatment of OA, and further clarified the pathophysiological significance of necroptosis.
