No abstract

Osteoarthritis (OA) has traditionally been defined as a non-inflammatory disease. Recently, many studies have demonstrated that OA also has an inflammatory component. BRD4, a member of the Bromodomain and Extra-Terminal Domain family, has emerged as an important regulator of some chronic inflammatory diseases. JQ1, an antagonist of BRD4, modulates transcription of several genes. Our study demonstrated that BRD4 is up-regulated in articular cartilage of OA. BRD4 inhibition attenuated the inflammation and catabolism of chondrocytes and suppressed NF-κB signalling pathway activation. In addition, BRD4 inhibition abolished the transcriptional activity of High Mobility Group Protein B1 (HMGB1). We identified HMGB1 as a direct target of BRD4. Genetic and pharmacological inhibition of BRD4 suppressed IL-1β-induced expression and translocation of HMGB1. Chromatin immunoprecipitation (ChIP) showed the enrichment of BRD4 around the HMGB1 upstream non-promoter region, which diminished with JQ1 treatment. Finally, haematoxylin & eosin and Safranin o/Fast Green staining demonstrated that JQ1 attenuates cartilage destruction in mice with anterior cruciate ligament transection without significant toxic effects. These studies highlighted the importance of BRD4 in the chronic inflammatory reactions of OA, which, as far as we know, was the first report of this finding, and suggested that BRD4 might be a novel potential therapeutic target for the treatment of OA.

No abstract

Osteoarthritis (OA) is a common degenerative disease characterized by the progressive destruction both articular cartilage and the subchondral bone. The agents that can effectively suppress chondrocyte degradation and subchondral bone loss are crucial for the prevention and treatment of OA. Oxymatrine (OMT) is a natural compound with anti‐inflammatory and antitumour properties. We found that OMT exhibited a strong inhibitory effect on LPS‐induced chondrocyte inflammation and catabolism. To further support our results, fresh human cartilage explants were treated with LPS to establish an ex vivo degradation model, and the results revealed that OMT inhibited the catabolic events of LPS‐stimulated human cartilage and substantially attenuated the degradation of articular cartilage ex vivo. As subchondral bone remodelling is involved in OA progression, and osteoclasts are a unique cell type in bone resorption, we investigated the effects of OMT on osteoclastogenesis, and the results demonstrated that OMT suppresses RANKL‐induced osteoclastogenesis by suppressing the RANKL‐induced NFATc1 and c‐fos signalling pathway in vitro. Further, we found that the anti‐inflammatory and anti‐osteoclastic effects of oxymatrine are mediated via the inhibition of the NF‐κB and MAPK pathways. In animal studies, OMT suppressed the ACLT‐induced cartilage degradation, and TUNEL assays further confirmed the protective effect of OMT on chondrocyte apoptosis. MicroCT analysis revealed that OMT had an attenuating effect on ACLT‐induced subchondral bone loss in vivo. Taken together, these results show that OMT interferes with the vicious cycle associated with OA and may be a potential therapeutic agent for abnormal subchondral bone loss and cartilage degradation in osteoarthritis.

Background:Knee osteoarthritis (KOA) is a chronic joint disease that manifests as knee pain as well as different degrees of lower limb swelling, stiffness, and movement disorders. The therapeutic goal is to alleviate or eliminate pain, correct deformities, improve or restore joint functions, and improve the quality of life. This study aimed to evaluate the efficacy and safety of Zhuanggu joint capsules combined with celecoxib and the benefit of treatment with Zhuanggu alone for KOA.Methods:This multi-center, randomized, double-blind, double-dummy, parallel controlled trial, started from December 2011 to May 2014, was carried out in 6 cities, including Beijing, Shanghai, Chongqing, Changchun, Chengdu, and Nanjing. A total of 432 patients with KOA were divided into three groups (144 cases in each group). The groups were treated, respectively, with Zhuanggu joint capsules combined with celecoxib capsule simulants, Zhuanggu joint capsules combined with celecoxib capsules, and celecoxib capsules combined with Zhuanggu joint capsule simulants for 4 weeks consecutively. The improvement of Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and the decreased rates in each dimension of WOMAC were evaluated before and after the treatment. Intergroup and intragroup comparisons of quantitative indices were performed. Statistically significant differences were evaluated with pairwise comparisons using Chi-square test (or Fisher's exact test) and an inspection level of α = 0.0167.Results:Four weeks after treatment, the total efficacies of Zhuanggu group, combination group, and celecoxib group were 65%, 80%, and 64%, respectively, with statistically significant differences among the three groups (P = 0.005). Intergroup pairwise comparisons showed that the total efficacy of the combination group was significantly higher than that of the Zhuanggu (P = 0.005) and celecoxib (P = 0.003) groups. The difference between the latter two groups was not statistically significant (P > 0.0167). Four weeks after discontinuation, the efficacies of the three groups were 78%, 95%, and 65%, respectively, with statistically significant differences (P < 0.0001). Intergroup pairwise comparisons revealed that the efficacy of the combination group was significantly better than that of the Zhuanggu and the celecoxib groups (P < 0.0001). The difference between the latter two groups was not statistically significant (P > 0.0167). The incidences of adverse events in Zhuanggu group, combination group, and celecoxib group were 8.5%, 8.5%, and 11.1%, respectively, with insignificant differences (P > 0.05).Conclusions:Zhuanggu joint capsules alone or combined with celecoxib showed clinical efficacy in the treatment of KOA. The safety of Zhuanggu joint capsules alone or combined with celecoxib was acceptable.Trial Registration:Chinese Clinical Trial Registry, ChiCTR-IPR-15007267; http://www.medresman.org/uc/project/projectedit.aspx?proj=1364.

Objective: To evaluate the anti-inflammatory effectiveness of celecoxib and its effect on the rehabilitation of joint function after total knee arthroplasty. Methods: 72 patients presented between 2016 and 2017 and were divided into two groups. The experimental group was given 200 mg celecoxib twice daily with tramadol hydrochloride 50 mg twice daily (as required); the control group was given tramadol hydrochloride 50 mg twice daily for 6 weeks from the first day after total knee arthroplasty. Skin temperature around the knee was measured 1 day before surgery, on postoperative days 1 and 3, and at weeks 1, 2, and 6. Inflammatory markers (white blood cell count, C-reactive protein, erythrocyte sedimentation rate, and interleukin-6) were measured preoperatively, on postoperative day 3, and at weeks 1 and 6. Knee Society Score was recorded preoperatively and at postoperative weeks 1, 2, and 6. Results: Except for preoperative skin temperature, the recorded skin temperatures of the experimental group were significantly different compared to those of the control group (p = 0.001, 0.024, 0.030, 0.041, 0.047, respectively). Levels of C-reactive protein were significantly different at the 1st and the 6th week after surgery, differing by 19.3 ± 4.64 mg/L (p < 0.001) and 2.6 ± 0.92 mg/L (p = 0.006). Levels of interleukin-6 showed a significant difference of 6.61 ± 2.36 pg/mL (p = 0.007) at the 1st week after surgery. Until the 6th week after surgery, the erythrocyte sedimentation rate in the experimental group and the control group differed by 17 ± 4.6 mm/h (p = 0.001). Conclusions: Celecoxib has a significant inhibitory effect on postoperative aseptic inflammation.

Objective: To investigate the influence of body mass index (BMI) and hip anatomy on direct anterior approach (DAA) total hip replacement. Subjects and Methods: The study is a retrospective analysis of 124 cases of DAA total hip replacement from 2009 to 2012. The BMI, the ratio of the greater trochanter (GT) and anterior superior iliac spine (ASIS) bilaterally (GT/ASIS), and the vertical distance between the ASIS and GT (AGVD) were obtained from medical records. All cases were categorized into three groups (43, 49, and 32 cases in each group, respectively) based on BMI (BMI <18.5, BMI 18.5-25, and BMI >25) or divided into two groups based on GT/ASIS (≤1.17 or >1.17) or AGVD (≤86 or >86 mm). Operating time, intraoperative bleeding, and surgical complications were compared between different groups. Results: A longer average operating time, more intraoperative bleeding, and a higher rate of complications were observed in the group with the highest BMI. The complications included a case of intraoperative femur fracture, a wound hematoma, and a lateral femoral cutaneous nerve injury. The group with higher GT/ASIS had a shorter average operating time, less bleeding, and a lower complication rate than the group with lower GT/ASIS. Moreover, the group with higher AGVD showed a shorter average operating time, less bleeding, and a lower complication rate compared with the group with lower AGVD. Conclusion: Our study suggests that lower BMI and larger GT/ASIS and AGVD are associated with a shorter operating time, less bleeding, and a lower complication rate in DAA total hip replacement. These findings are valuable for clinicians to make the appropriate choice of surgery types for different individuals.

Objectives Aseptic loosening (AL) is the most common reason of total hip arthroplasty (THA) failure and revision surgery. Osteolysis, caused by wear particles released from implant surfaces, has a vital role in AL. Although previous studies suggest that wear particles always lead to osteoblast programmed death in the process of AL, the specific mechanism remains incompletely understood and osteoblast ferroptosis maybe a new mechanism of AL. Materials and Methods CoCrMo nanoparticles (CoNPs) were prepared to investigate the influence of ferroptosis in osteoblasts and calvaria resorption animal models. Periprosthetic osteolytic bone tissue was collected from patients who underwent AL after THA to verify osteoblast ferroptosis. Results Our study demonstrated that CoNPs induced significant ferroptosis in osteoblasts and particles induced osteolysis (PIO) animal models. Blocking ferroptosis with specific inhibitor Ferrostatin‐1 dramatically reduced particle‐induced ferroptosis in vitro. Moreover, in osteoblasts, CoNPs significantly downregulated the expression of Nrf2 (nuclear factor erythroid 2‐related factor 2), a core element in the antioxidant response. The overexpression of Nrf2 by siKeap1 or Nrf2 activator Oltipraz obviously upregulated antioxidant response elements (AREs) and suppressed ferroptosis in osteoblasts. Furthermore, in PIO animal models, the combined utilization of Ferrostatin‐1 and Oltipraz dramatically ameliorated ferroptosis and the severity of osteolysis. Conclusions These results indicate that CoNPs promote osteoblast ferroptosis by regulating the Nrf2‐ARE signalling pathway, which suggests a new mechanism underlying PIO and represents a potential therapeutic approach for AL.