Reactive oxygen species (ROS) are implicated in induction of inflammatory response and cartilage degradation in osteoarthritis (OA). Melatonin has been shown to improve the chondrogenic differentiation and promote cartilage matrix synthesis in mesenchymal stem cells. However, the underlying mechanisms of melatonin-regulated antioxidant activity in OA cartilage are not known. The aim of this study was to explore the effect of melatonin on nuclear factor-erythroid 2-related factor 2 (NRF2), a key antioxidant transcription factor, and its target antioxidant genes in early-stage OA cartilage. Primary chondrocytes were isolated from rats with surgically induced OA. In vitro treatment of melatonin significantly increased cartilage matrix synthesis and up-regulated antioxidant enzymes, mainly heme oxygenase 1 (HO-1), while decreasing matrix degradation enzymes and intracellular ROS. In vivo intra-articular injection of melatonin effectively ameliorated cartilage degeneration in an experimental rat OA model. Inhibition of melatonin membrane receptors by Luzindole or 4-P-PDOT reversed the beneficial effects of melatonin on cartilage matrix synthesis, implying that melatonin receptor-mediated pathway is involved in its anti-arthritic effects. Interestingly, melatonin showed no significant effect on the mRNA level of Nrf2 but significantly increased its protein level. Silencing of Nrf2 or HO-1 expression abolished the protective effects of melatonin, as shown by increased ROS levels and matrix degradation enzyme expression. Microarray assays revealed that miR-146a, a predicted target for Nrf2, was significantly up-regulated in OA chondrocytes but was remarkedly reduced by melatonin treatment. Over-expression of miR-146a diminished the protective effects of melatonin by inhibiting NRF2 expression and aggravating OA-induced cartilage degradation. These findings demonstrate that melatonin supports the anabolic metabolism of cartilage matrix in OA chondrocytes by enhancing the protein levels of NRF2 via suppressing miR-146a. Melatonin-mediated activation of the NRF2/HO-1 axis prevents cartilage degeneration and represents a promising therapeutic target for treatment of early-stage OA.

Background: Postoperative delirium (POD) is widely reported as a common postoperative complication following total joint arthroplasty (TJA) of the hip and knee in elderly patients, leading to many adverse effects. We sought to investigate predictors of delirium after TJA. Methods: PubMed, EMBASE, Cochrane Library and Web of Science were searched up to 2020 for studies examining POD following TJA in elderly patients. Pooled odds ratio (OR) and mean difference (MD) of those who experienced delirium compared to those who did not were calculated for each variable. The Newcastle-Ottawa Scale (NOS) was used for the study quality evaluation. Results: Fifteen studies with 31 potential factors were included. In the primary analysis, 9 factors were associated with POD, comprising advanced age (MD 3.81; 95% confidence interval (CI) 1.80–5.83), dementia (OR 24.85; 95% CI 7.26–85.02), hypertension (OR 2.26; 95% CI 1.31–3.89), diabetes (OR 2.02; 95% CI 1.15–3.55), stroke (OR 14.61; 95% CI 5.26–40.55), psychiatric illness (OR 2.72; 95% CI 1.45–5.08), use of sedative-hypnotics (OR 6.42; 95% CI 2.53–16.27), lower preoperative levels of hemoglobin (MD − 0.56; 95% CI − 0.89−− 0.22), and lower preoperative mini-mental state examination score (MD − 0.40; 95% CI − 0.69−− 0.12). Twelve studies were included in the systematic review, of which 24 factors were additionally correlated with POD using single studies. Conclusions: Strategies and interventions should be implemented for the elderly patients receiving TJA surgeries with potential predictors identified in this meta-analysis.

Millions of people worldwide suffer from osteoporosis, which causes bone fragility and increases the risk of fractures. Osteoporosis is closely related to the inhibition of osteogenesis and the enhancement of osteoclastogenesis. In addition, chronic inflammation and macrophage polarization may contribute to osteoporosis as well. Macrophages, crucial to inflammatory responses, display different phenotypes under the control of microenvironment. There are two major phenotypes, classically activated macrophages (M1) and alternatively activated macrophages (M2). Generally, M1 macrophages mainly lead to bone resorption, while M2 macrophages result in osteogenesis. M1/M2 ratio reflects the “fluid” state of macrophage polarization, and the imbalance of M1/M2 ratio may cause disease such as osteoporosis. Additionally, antioxidant drugs, such as melatonin, are applied to change the state of macrophage polarization and to treat osteoporosis. In this review, we introduce the mechanisms of macrophage polarization‐mediated bone resorption and bone formation and the contribution to the clinical strategies of osteoporosis treatment.

Intervertebral disc degeneration (IVDD) is a prevalent musculoskeletal disorder that involves the excessive accumulation of reactive oxygen species (ROS), resulting in mitochondrial dysfunction and matrix metabolism imbalance in nucleus pulposus cells (NPCs). Selenium, an indispensable trace element, plays a crucial role in maintaining mitochondrial redox homeostasis by being incorporated into antioxidant selenoproteins as selenocysteine. In this study, we employed a straightforward synthesis method to produce selenium nanoparticles (SeNPs) with consistent size and distribution, and evaluated their potential protective effects in ameliorating IVDD. In a simulated inflammatory environment induced by interleukin-1beta (IL-1β) in vitro, SeNPs demonstrated a protective effect on the matrix synthesis capacity of NPCs through the up-regulation of aggrecan and type II collagen, while concurrently suppressing the expression of matrix degradation enzymes including MMP13 and ADAMTS5. Additionally, SeNPs preserved mitochondrial integrity and restored impaired mitochondrial energy metabolism by activating glutathione peroxidase1 (GPX1) to rebalance redox homeostasis. In a rat lumbar disc model induced by puncture, the local administration of SeNPs preserved the hydration of nucleus pulposus tissue, promoted matrix deposition, and effectively mitigated the progression of IVDD. Our results indicate that the enhancement of GPX1 by SeNPs may offer a promising therapeutic approach for IVDD by restoring mitochondrial function and redox homeostasis.

Osteoarthritis (OA) is characterized by the progressive destruction of articular cartilage, which is involved in the imbalance between extracellular matrix (ECM) synthesis and degradation. MicroRNA-140-5p (miR-140) is specifically expressed in cartilage and plays an important role in OA-induced matrix degradation. The aim of this study was to investigate (1) whether intra-articular injection of melatonin could ameliorate surgically induced OA in mice and (2) whether melatonin could regulate matrix-degrading enzymes at the posttranscriptional level by targeting miR-140. In an in vitro OA environment induced by interleukin-1 beta (IL-1β), melatonin treatment improved cell proliferation of human chondrocytes, promoted the expression of cartilage ECM proteins (e.g., type II collagen and aggrecan), and inhibited the levels of IL-1β-induced proteinases, such as matrix metalloproteinase 9 (MMP9), MMP13, ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4), and ADAMTS5. Both the microarray and polymerase chain reaction (PCR) experiments revealed that miR-140 was a melatonin-responsive microRNA and melatonin upregulated miR-140 expression, which was suppressed by IL-1β stimulation. In vivo experiments demonstrated that intra-articular injection of melatonin prevented disruptions of cartilage matrix homeostasis and successfully alleviated the progression of surgery-induced OA in mice. Transfection of miR-140 antagomir completely counteracted the antiarthritic effects of melatonin by promoting matrix destruction. Our findings demonstrate that melatonin protects the articular cartilage from OA-induced degradation by targeting miR-140, and intra-articular administration of melatonin may benefit patients suffering from OA.