NCOA3 Loss Disrupts Molecular Signature of Chondrocytes and Promotes Posttraumatic Osteoarthritis Progression.

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. 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. 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-1ß, 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. 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.

Baicalin effects on rats with spinal cord injury by anti-inflammatory and regulating the serum metabolic disorder.

Baicalin had neuroprotective effects on inhibiting neuronal cell apoptosis induced by spinal cord ischemic injury. This study aimed to explore the protective effects of Baicalin on rats with spinal cord injury (SCI) and its mechanism of action. The recovery of spinal cord nerve function in rats was evaluated by the Basso, Beattie, and Bresnahan (BBB) score and the combine behavioral score (CBS). The expressions of cytokines tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 were detected by the enzyme-linked immunosorbent assay method. Expressions of inflammation-related proteins were detected by Western blot. Multivariate statistical analysis was performed for serum metabolites. The BBB and CBS score results showed that Baicalin had a certain improvement on rats with SCI. SCI symptoms were significantly improved in low-dose and high-dose groups. The levels of TNF-α, IL-1ß, and IL-6 in the SCI group were significantly increased. The expressions of NF-κB p65, NF-κB p50, p-IκBα, and IKKα in the SCI group showed the opposite trend compared with the low-dose and high-dose groups. Compared with the sham group, glutamine, levels of 3-OH-butyrate, N-acetylaspartate, and glutathione were significantly reduced, and the levels of glutamate and betaine were significantly increased in the SCI group. When Baicalin was administered, the contents of glutamine synthase (GS) and glutaminase (GLS) were significantly reduced, indicating that Baicalin had the effect of improving GS and GLS. Baicalin has protective effects on improving SCI and lower extremity motor function, has a significant anti-inflammatory effect, and regulates the serum metabolic disorder caused by SCI in rats.