Sappanone A Alleviated IL-1ß-Induced Inflammation in OA Chondrocytes through Modulating the NF-κB and Nrf2/HO-1 Pathways.

Objective: This study was to examine the anti-inflammatory effect of sappanone A on interleukin- (IL-) 1ß-stimulated osteoarthritis (OA) chondrocytes. Methods: Chondrocytes were pretreated with sappanone A for 2 h before subsequent IL-1ß stimulation. The mRNA expression levels of iNOs, COX-2, aggrecan, and collagen-II were measured with qRT-PCR. The levels of TNF-α, IL-6, IL-8, MMP-3, and MMP-13 were determined by ELISA. The protein levels of iNOs, COX-2, ADAMTS-4, ADAMTS-5, aggrecan, collagen-II, p-p65, p65, IκBα, Nrf2, and HO-1 were assessed by Western blot. Results: Sappanone A inhibited the IL-1ß-stimulated production of NO, PGE2, iNOS, COX-2, TNF-α, IL-6, and IL-8 in OA chondrocytes. In addition, sappanone A suppressed the expression of MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 in IL-1ß-stimulated OA chondrocytes. The degradation of ECM components was reversed by sappanone A. Sappanone A prevented NF-κB activation while enhanced Nrf2/HO-1 activation in IL-1ß-treated chondrocytes. Conclusion: Sappanone A may be a potent therapeutic agent for OA.

SUMO-modified bone marrow mesenchymal stem cells promoted the repair of articular cartilage in rats.

Articular cartilage damage can lead to joint deformity, pain, and severe dysfunction. However, due to the lack of blood vessels and nerves in articular cartilage, the self-healing capacity of damaged cartilage is limited. In this study, we overexpressed small ubiquitin-like modifier (SUMO)1, SUMO2/3, and SUMO1/2/3 in bone marrow mesenchymal stem cells (BMSCs). Then, these cells were inoculated on surfaces of different hardness, and their differentiation into chondrocytes, hypoxic tolerance ability, and inflammatory response was detected. Finally, BMSCs were transplanted into the injured knee joint cavity of the rats, and the repair was evaluated. We found that BMSCs overexpressing SUMO1 were more likely to differentiate into articular cartilage along with the hardness of the surface, while BMSCs overexpressing SUMO2/3 could reduce inflammation response and improve the damaged cartilage microenvironment. In the rat model, BMSCs overexpressing SUMO1/2/3 transplanted on injured articular cartilage surface showed better survival, less inflammatory response, and improved tissue repair capability. In conclusion, BMSCs overexpressing SUMO are more tolerant to hypoxia conditions, and have stronger repair ability for damaged chondrocytes in vitro and for articular cartilage injury model in rats, and are excellent seed cells for repairing articular cartilage.

GADD45ß-I attenuates oxidative stress and apoptosis via Sirt3-mediated inhibition of ER stress in osteoarthritis chondrocytes.

Osteoarthritis (OA) is one of the most characterized joint diseases associated with chondrocyte apoptosis. JNK plays an important role in apoptosis in many pathological conditions, but systemic inhibition of JNK was shown to result in detrimental side effects. MAPK kinase 7 (MKK7) is a direct upstream kinase that regulates JNK and has been shown to activate JNK specifically under toxic conditions. In this study, we investigated the effect of GADD45ß-I, a cell-permeable inhibitor targeted for MKK7, on IL-1ß-induced cytotoxicity in rat chondrocytes. The results showed that IL-1ß exposure resulted in toxicity in a dose-dependent manner, which was nullified by endoplasmic reticulum (ER) stress inhibitors. GADD45ß-I significantly preserved cell survival, inhibited oxidative injury and reduced apoptosis after IL-1ß treatment. ER stress in chondrocytes was attenuated by GADD45ß-I, as evidenced by reduced levels of GRP78 and CHOP, as well as decreased caspase-12 cleavage. In addition, GADD45ß-I increased the enzymatic activities of mitochondrial antioxidant enzymes, including IDH2, GSH-Px and SOD2. GADD45ß-I significantly upregulated the expression of Sirt3 and attenuated IL-1ß-induced acetylation of SOD2. Furthermore, GADD45ß-I-induced inhibition of ER stress and protection in chondrocytes were partially reversed by knockdown of Sirt3. In conclusion, our data indicated that GADD45ß-I protected chondrocytes against IL-1ß through Sirt3-mediated inhibition of ER stress. Targeting MKK7 might be an ideal therapeutic strategy for reducing chondrocyte apoptosis in OA.

Is cervical disc arthroplasty superior to fusion for treatment of symptomatic cervical disc disease? A meta-analysis.

BACKGROUND: As the current standard treatment for symptomatic cervical disc disease, anterior cervical decompression and fusion may result in progressive degeneration or disease of the adjacent segments. Cervical disc arthroplasty was theoretically designed to be an ideal substitute for fusion by preserving motion at the operative level and delaying adjacent level degeneration. However, it remains unclear whether arthroplasty achieves that aim. QUESTIONS/PURPOSES: We investigated whether cervical disc arthroplasty was associated with (1) better function (neck disability index, pain assessment, SF-36 mental and physical health surveys, neurologic status) than fusion, (2) a lower incidence of reoperation and major complications, and (3) a lower risk of subsequent adjacent segment degeneration. METHODS: We conducted a comprehensive search in MEDLINE(®), EMBASE, and Cochrane Central Register of Controlled Trials and identified 503 papers. Of these, we identified 13 reports from 10 randomized controlled trials involving 2227 patients. We performed a meta-analysis of functional scores, rates of reoperation, and major complications. The strength of evidence was evaluated by using GRADE profiler software. Of the 10 trials, six trials including five prospective multicenter FDA-regulated studies were sponsored by industry. The mean follow-ups of the 10 trials ranged from 1 to 5 years. RESULTS: Compared with anterior cervical decompression and fusion, cervical disc arthroplasty had better mean neck disability indexes (95% CI, -0.25 to -0.02), neurologic status (risk ratio [RR], 1.04; 95% CI, 1.00-1.08), with a reduced incidence of reoperation related to the index surgery (RR, 0.42; 95% CI, 0.22-0.79), and major surgical complications (RR, 0.45; 95% CI, 0.27-0.75) at a mean of 1 to 3 years. However, the operation rate at adjacent levels after two procedures was similar (95% CI, 0.31-1.27). The three studies with longer mean follow-ups of 4 to 5 years also showed similar superiority of all four parameters of cervical disc arthroplasty compared with fusion. CONCLUSIONS: For treating symptomatic cervical disc disease, cervical disc arthroplasty appears to provide better function, a lower incidence of reoperation related to index surgery at 1 to 5 years, and lower major complication rates compared with fusion. However, cervical disc arthroplasty did not reduce the reoperation rate attributable to adjacent segment degeneration than fusion. Further, it is unclear whether these differences in subsequent surgery including arthroplasty revisions will persist beyond 5 years.