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NCOA3 Loss Disrupts Molecular Signature of Chondrocytes and Promotes Posttraumatic Osteoarthritis Progression.
- Source :
-
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology [Cell Physiol Biochem] 2018; Vol. 49 (6), pp. 2396-2413. Date of Electronic Publication: 2018 Sep 27. - Publication Year :
- 2018
-
Abstract
- Background/aims: Osteoarthritis (OA) is the most common joint disease. Recently, a novel variant near the nuclear receptor coactivator 3 (NCOA3) has been identified in association with greater risk of developing OA. However, how NCOA3 is regulated in chondrocytes and involved in OA pathogenesis remain elusive.<br />Methods: The expression and DNA methylation of NCOA3 in knee OA cartilage and in vitro dedifferentiated chondrocytes with or without rs6094710 SNP were analyzed by qRT-PCR, immunoblotting, methylation-specific PCR and bisulfite sequencing. NCOA3 was depleted by siRNA or shRNA or inhibited by a chemical inhibitor to assess its role in chondrocyte dedifferentiation or OA pathogenesis in posttraumatic OA animal model established by cruciate ligament transection surgery.<br />Results: We found that compared with normal counterparts, samples with rs6094710 SNP failed to upregulate NCOA3. Further evidence associated this phenotype with DNMT1-mediated hypermethylation in gene promoter region. Moreover, we showed that NCOA3 maintained the molecular signature of chondrocytes dedifferentiating in vitro or exposed to IL-1β, nevertheless, NCOA3 appeared dispensable for preventing OA initiation, since NCOA3 loss did not trigger OA in young mice. Instead, NCOA3 loss promoted posttraumatic OA progression, and in parallel, enhanced NF-κB activation. Finally, the promoted posttraumatic OA progression was significantly retarded when administrated with NF-κB pathway inhibitor, suggesting that NCOA3 lose promotes posttraumatic OA at least partially by enhancing NF-κB activation.<br />Conclusion: Thus, our findings indicate a critical role of NCOA3 in chondrocytes, and imply that manipulating NCOA3 might present a potential therapeutic approach to interfere OA progression.<br /> (© 2018 The Author(s). Published by S. Karger AG, Basel.)
- Subjects :
- Animals
Cartilage, Articular cytology
Cell Dedifferentiation drug effects
Cells, Cultured
Chondrocytes cytology
Chondrocytes metabolism
DNA (Cytosine-5-)-Methyltransferase 1 metabolism
DNA Methylation
Genotype
Humans
Interleukin-1beta pharmacology
Knee pathology
Male
Mice
Mice, Inbred C57BL
NF-kappa B metabolism
Nuclear Receptor Coactivator 3 antagonists & inhibitors
Nuclear Receptor Coactivator 3 genetics
Osteoarthritis pathology
Polymorphism, Single Nucleotide
RNA Interference
RNA, Small Interfering metabolism
Nuclear Receptor Coactivator 3 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1421-9778
- Volume :
- 49
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 30261507
- Full Text :
- https://doi.org/10.1159/000493839