51. Inhibition of nuclear receptor RORα attenuates cartilage damage in osteoarthritis by modulating IL-6/STAT3 pathway.
- Author
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Liang T, Chen T, Qiu J, Gao W, Qiu X, Zhu Y, Wang X, Chen Y, Zhou H, Deng Z, Li P, Xu C, Peng Y, Liang A, Su P, Gao B, and Huang D
- Subjects
- Aged, Animals, Base Sequence, Benzamides chemistry, Benzamides pharmacology, Cartilage, Articular drug effects, Cartilage, Articular metabolism, Chondrocytes metabolism, Chondrocytes pathology, Disease Models, Animal, Down-Regulation drug effects, Female, Fluorocarbons chemistry, Fluorocarbons pharmacology, Humans, Interleukin-6 genetics, Male, Mice, Inbred C57BL, Models, Biological, Nuclear Receptor Subfamily 1, Group F, Member 1 agonists, Nuclear Receptor Subfamily 1, Group F, Member 1 antagonists & inhibitors, Osteoarthritis genetics, Phosphorylation drug effects, Promoter Regions, Genetic genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Severity of Illness Index, Sulfonamides chemistry, Sulfonamides pharmacology, Thiophenes chemistry, Thiophenes pharmacology, Mice, Cartilage, Articular pathology, Interleukin-6 metabolism, Nuclear Receptor Subfamily 1, Group F, Member 1 metabolism, Osteoarthritis metabolism, Osteoarthritis pathology, STAT3 Transcription Factor metabolism, Signal Transduction
- Abstract
Osteoarthritis (OA) is characterized by cartilage destruction, chronic inflammation, and local pain. Evidence showed that retinoic acid receptor-related orphan receptor-α (RORα) is crucial in cartilage development and OA pathogenesis. Here, we investigated the role and molecular mechanism of RORα, an important member of the nuclear receptor family, in regulating the development of OA pathologic features. Investigation into clinical cartilage specimens showed that RORα expression level is positively correlated with the severity of OA and cartilage damage. In an in vivo OA model induced by anterior crucial ligament transaction, intra-articular injection of si-Rora adenovirus reversed the cartilage damage. The expression of cartilage matrix components type II collagen and aggrecan were elevated upon RORα blockade. RNA-seq data suggested that the IL-6/STAT3 pathway is significantly downregulated, manifesting the reduced expression level of both IL-6 and phosphorylated STAT3. RORα exerted its effect on IL-6/STAT3 signaling in two different ways, including interaction with STAT3 and IL-6 promoter. Taken together, our findings indicated the pivotal role of the RORα/IL-6/STAT3 axis in OA progression and confirmed that RORα blockade improved the matrix catabolism in OA chondrocytes. These results may provide a potential treatment target in OA therapy., (© 2021. The Author(s).)
- Published
- 2021
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