G protein-coupled receptor 30 activation inhibits ferroptosis and protects chondrocytes against osteoarthritis.

Background: Osteoarthritis (OA) is the most common joint disease worldwide, but its cause remains unclear. Oestrogen protects against OA, but its clinical use is limited. G protein-coupled receptor 30 (GPR30) is a receptor that binds oestrogen, and GPR30 treatment has benefitted patients with some degenerative diseases. However, its effects on OA prevention and treatment remain unclear. Moreover, several studies have found that activation of estrogen receptors exerting anti-ferroptosis effects, which plays an important role in chondrocyte survival. Therefore, this study explored the general and ferroptosis-related effects and mechanisms of GPR30 in OA. Methods: Genome-wide RNA sequencing, western blotting, and immunohistochemistry were used to evaluate GPR30 expression and ferroptosis-related indicators in cartilage tissues from clinical patients. Next, we investigated the effects of G1 (a GPR30 receptor agonist) on the function and pathology of OA in an animal model. We also treated chondrocytes with erastin (ferroptosis agonist) plus G1, G15 (GPR30 receptor antagonist), GPR30 short hairpin RNA, or ferrostatin-1 (ferroptosis inhibitor), then measured cell viability and ferroptosis-related indices and performed proteomics analyses. Finally, western blotting and reverse transcription-polymerase chain reaction were used to assess the effects of G1 on yes-associated protein 1 (YAP1) and ferritin heavy chain 1 (FTH1) expression. Results: GPR30 expression was lower in the OA cartilage tissues than in the normal tissues, and G1 treatment significantly improved the locomotor ability of mice. Moreover, chondrocyte cell viability significantly decreased after erastin treatment, but G1 treatment concentration-dependently mitigated this effect. Furthermore, G1 treatment decreased phosphorylated YAP1 expression, increased activated YAP1 expression, and increased FTH1 transcription and protein expression, protecting against ferroptosis. Conclusion: GPR30 activation inhibited ferroptosis in chondrocytes by suppressing YAP1 phosphorylation, which regulates FTH1 expression.The Translational Potential of this Article: These results provide a novel potential target for therapeutic OA interventions.

Association of Use of Tourniquets During Total Knee Arthroplasty in the Elderly Patients With Post-operative Pain and Return to Function.

Objective: During total knee arthroplasty (TKA), tourniquet may negatively impact post-operative functional recovery. This study aimed at investigating the effects of tourniquet on pain and return to function. Methods: Pubmed, Embase, and Cochrane Library were comprehensively searched for randomized controlled trials (RCTs) published up to February 15th, 2020. Search terms included; total knee arthroplasty, tourniquet, and randomized controlled trial. RCTs evaluating the efficacies of tourniquet during and after operation were selected. Two reviewers independently extracted the data. Effect estimates with 95% CIs were pooled using the random-effects model. Dichotomous data were calculated as relative risks (RR) with 95% confidence intervals (CI). Mean differences (MD) with 95% CI were used to measure the impact of consecutive results. Primary outcomes were the range of motion (ROM) and visual analog scale (VAS) pain scores. Results: Thirty-three RCTs involving a total of 2,393 patients were included in this study. The mean age is 65.58 years old. Compared to no tourniquet group, the use of a tourniquet resulted in suppressed ROM on the 3rd post-operative day [MD, -4.67; (95% CI, -8.00 to -1.35)] and the 1st post-operative month [MD, -3.18; (95% CI, -5.92 to -0.44)]. Pain increased significantly when using tourniquets on the third day after surgery [MD, 0.39; (95% CI, -0.19 to 0.59)]. Moreover, tourniquets can reduce intra-operative blood loss [MD, -127.67; (95% CI, -186.83 to -68.50)], shorter operation time [MD, -3.73; (95% CI, -5.98 to -1.48)], lower transfusion rate [RR, 0.85; (95% CI, 0.73-1.00)], higher superficial wound infection rates RR, 2.43; [(5% CI, 1.04-5.67)] and higher all complication rates [RR, 1.98; (95% CI, 1.22-3.22)]. Conclusion: Moderate certainty evidence shows that the use of a tourniquet was associated with an increased risk of higher superficial wound infection rates and all complication rates. Therefore, the findings did not support the routine use of a tourniquet during TKA.

The aqueous extract of Angelica sinensis, a popular Chinese herb, inhibits wear debris-induced inflammatory osteolysis in mice.

BACKGROUND: More and more studies have shown Angelica sinensis' (AS) therapeutic action on chronic inflammatory diseases in recent years. We investigated effects of aqueous extract of AS on inflammatory cytokines release and wear debris particles-induced osteolysis. MATERIALS AND METHODS: Ultra high molecular weight polyethylene (UHMWPE) particles were used to induce inflammation in RAW264.7 cell and C57BL/J6 mice. AS extract was obtained through a series of purification steps, and divided into high dose group and low dose group during the research of cell culture, tissue culture, and animal treatment. After 72 h culture with optimal particles, supernatants were collected for cytokine analysis. Calvaria were harvested from the mice model after 10 d treatment with the AS extract. Six calvaria of each group were cultured into medium for 72 h for analyzing cytokine generated in vivo. Histologic analyses and micro-computed tomography (micro-CT) scan were used to determine osteoclastogenesis and inflammatory bone resorption. RESULTS: Concentration of tumor necrosis-alpha (TNF-α) and interleukin-1beta (IL-1ß) was significantly attenuated by AS extract both in vitro and in vivo. The osteolysis area and the osteoclast numbers were decreased from 0.406 ± 0.0799 to 0.117 ± 0.0103 mm(2), and from 22.7 ± 5.0 to 11.3 ± 1.8, respectively (P < 0.01). Compared with the control group, the protection effects of AS extract was further confirmed with data of the more accurate 3-dimension micro-CT reconstruction. CONCLUSIONS: This study suggests a potential resolution of inhibiting wear debris particles-induced inflammatory bone resorption, as well as a possible way of inhibiting aseptic loosening after joint replacement surgery.