Rotator cuff repair with all-suture anchor enhances biomechanical properties and tendon-bone integration in a rabbit model.

Background: All-suture anchor (ASA) is a special type of suture anchor. It has been used to repair rotator cuff tears (RCTs). However, mechanical properties and tendon-bone integration at different time postoperatively remains to be unclear. Methods: Mechanical testing and water contact angle measurements were conducted for ASA. In vitro biocompatibility was assessed using rat bone marrow stem cells (BMSCs), including live/dead cell staining and Cell Counting Kit-8 assays. ASA was implanted for rotator cuff repair (ASA group) in a New Zealand White rabbit model of RCTs, and a natural rotator cuff was used as a control (natural group). The animals were sacrificed, and tissue samples were harvested for biomechanical, radiographic, and histological analysis at 4, 8, and 12 weeks postoperatively. Results: ASA was hydrophobic and had a strong mechanical property in vitro. The biocompatibility analysis showed that ASA had no effect on the viability of BMSCs. Mechanical testing in vivo revealed that a gradually improved failure load of ASA group was 118.0 ± 22.53N at 12 weeks postoperatively, which was recovered to the natural group. Micro-CT analysis indicated that an initial decrease in BMD and trabecular quality following ASA implantation, with a slight recovery observed at 12 weeks. Additionally, histological analysis showed the tendon-bone interface gradually integrated in the ASA group. A significant increase in tendon-bone interface scores was found from 4 weeks to 12 weeks. Tendon maturing score also improved in the ASA group, and Type I collagen content recovered to 18.58 ± 4.378 % at 12 weeks and no different from that of the natural group. Conclusion: Rotator cuff repair with ASA in a rabbit model demonstrated the capacity to enhance biomechanical properties and tendon-bone integration.

Research progress of ultrasound in accurate evaluation of cartilage injury in osteoarthritis.

Osteoarthritis (OA) is a prevalent cause of joint algesia, loss of function, and disability in adults, with cartilage injury being its core pathological manifestation. Since cartilage damage is non-renewable, the treatment outcome in the middle and late stages of OA is unsatisfactory, which can be minimized by changing lifestyle and other treatment modalities if diagnosed and managed in the early stages, indicating the importance of early diagnosis and monitoring of cartilage injury. Ultrasound technology has been used for timely diagnosis and even cartilage injury treatment, which is convenient and safe for the patient owing to no radiation exposure. Studies have demonstrated the effectiveness of ultrasound and its various quantitative ultrasound parameters, like ultrasound roughness index (URI), reflection coefficient (R), apparent integrated backscatter (AIB), thickness, and ultrasound elastography, in the early and accurate assessment of OA cartilage pathological changes, including surface and internal tissue, hardness, and thickness. Although many challenges are faced in the clinical application of this technology in diagnosis, ultrasound and ultrasound-assisted techniques offer a lot of promise for detecting early cartilage damage in OA. In this review, we have discussed the evaluation of ultrasonic cartilage quantitative parameters for early pathological cartilage changes.

Synchronously in vivo real-time monitoring bacterial load and temperature with evaluating immune response to decipher bacterial infection.

Determining the precise course of bacterial infection requires abundant in vivo real-time data. Synchronous monitoring of the bacterial load, temperature, and immune response can satisfy the shortage of real-time in vivo data. Here, we conducted a study in the joint-infected mouse model to synchronously monitor the bacterial load, temperature, and immune response using the second near-infrared (NIR-II) fluorescence imaging, infrared thermography, and immune response analysis for 2 weeks. Staphylococcus aureus (S. aureus) was proved successfully labeled with glucose-conjugated quantum dots in vitro and in subcutaneous-infected model. The bacterial load indicated by NIR-II fluorescence imaging underwent a sharp drop at 1 day postinfection. At the same time, the temperature gap detected through infrared thermography synchronously brought by infection reached lowest value. Meanwhile, the flow cytometry analysis demonstrated that immune response including macrophage, neutrophil, B lymphocyte, and T lymphocyte increased to the peak at 1 day postinfection. Moreover, both M1 macrophage and M2 macrophage in the blood have an obvious change at ~ 1 day postinfection, and the change was opposite. In summary, this study not only obtained real-time and long-time in vivo data on the bacterial load, temperature gap, and immune response in the mice model of S. aureus infection, but also found that 1 day postinfection was the key time point during immune response against S. aureus infection. Our study will contribute to synchronously and precisely studying the complicated complex dynamic relationship after bacterial infection at the animal level.

Inversion Method for Transformer Winding Hot Spot Temperature Based on Gated Recurrent Unit and Self-Attention and Temperature Lag.

The hot spot temperature of transformer windings is an important indicator for measuring insulation performance, and its accurate inversion is crucial to ensure the timely and accurate fault prediction of transformers. However, existing studies mostly directly input obtained experimental or operational data into networks to construct data-driven models, without considering the lag between temperatures, which may lead to the insufficient accuracy of the inversion model. In this paper, a method for inverting the hot spot temperature of transformer windings based on the SA-GRU model is proposed. Firstly, temperature rise experiments are designed to collect the temperatures of the entire side and top of the transformer tank, top oil temperature, ambient temperature, the cooling inlet and outlet temperatures, and winding hot spot temperature. Secondly, experimental data are integrated, considering the lag of the data, to obtain candidate input feature parameters. Then, a feature selection algorithm based on mutual information (MI) is used to analyze the correlation of the data and construct the optimal feature subset to ensure the maximum information gain. Finally, Self-Attention (SA) is applied to optimize the Gate Recurrent Unit (GRU) network, establishing the GRU-SA model to perceive the potential patterns between output feature parameters and input feature parameters, achieving the precise inversion of the hot spot temperature of the transformer windings. The experimental results show that considering the lag of the data can more accurately invert the hot spot temperature of the windings. The inversion method proposed in this paper can reduce redundant input features, lower the complexity of the model, accurately invert the changing trend of the hot spot temperature, and achieve higher inversion accuracy than other classical models, thereby obtaining better inversion results.

Acetyl-11-keto-ß-boswellic acid restrains the progression of synovitis in osteoarthritis via the Nrf2/HO-1 pathway.

Synovial inflammation plays a key role in osteoarthritis (OA) pathogenesis. Fibroblast-like synoviocytes (FLSs) represent a distinct cell subpopulation within the synovium, and their unique phenotypic alterations are considered significant contributors to inflammation and fibrotic responses. The underlying mechanism by which acetyl-11-keto-ß-boswellic acid (AKBA) modulates FLS activation remains unclear. This study aims to assess the beneficial effects of AKBA through both in vitro and in vivo investigations. Network pharmacology evaluation is used to identify potential targets of AKBA in OA. We evaluate the effects of AKBA on FLSs activation in vitro and the regulatory role of AKBA on the Nrf2/HO-1 signaling pathway. ML385 (an Nrf2 inhibitor) is used to verify the binding of AKBA to its target in FLSs. We validate the in vivo efficacy of AKBA in alleviating OA using anterior cruciate ligament transection and destabilization of the medial meniscus (ACLT+DMM) in a rat model. Network pharmacological analysis reveals the potential effect of AKBA on OA. AKBA effectively attenuates lipopolysaccharide (LPS)-induced abnormal migration and invasion and the production of inflammatory mediators, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS) in FLSs, contributing to the restoration of the synovial microenvironment. After treatment with ML385, the effect of AKBA on FLSs is reversed. In vivo studies demonstrate that AKBA mitigates synovial inflammation and fibrotic responses induced by ACLT+DMM in rats via activation of the Nrf2/HO-1 axis. AKBA exhibits theoretical potential for alleviating OA progression through the Nrf2/HO-1 pathway and represents a viable therapeutic candidate for this patient population.

Injectable porous microspheres for articular cartilage regeneration through in situ stem cell recruitment and macrophage polarization.

In situ mesenchymal stem cells (MSCs) regenerative therapy holds promising potential for treating osteoarthritis. However, MSCs engraftment and intra-articular inflammation limit the therapeutic efficacy of this approach. This study introduces porous microspheres (PMs) composed of aldehyde-modified poly(lactic-co-glycolic acid), that encapsulate platelet derived growth factor-AB and kartogenin. Metformin (Met) is also incorporated onto the microsphere through a Schiff base reaction to create PMs@Met. In vitro, in vivo and ex experiments revealed that PMs@Met can be injected into the joint cavity, effectively recruiting endogenous MSCs in situ. This approach creates a favorable environment for MSCs proliferation. It also controls the intra-articular inflammatory environment by modulating the polarization of synovial macrophages, ultimately promoting cartilage repair. In summary, our study presents an innovative tissue engineering strategy for the treatment of osteoarthritis-induced articular cartilage injuries. STATEMENT OF SIGNIFICANCE: Cell therapy using autologous mesenchymal stem cells (MSCs) has potential to slow the progression of osteoarthritis (OA). Nonetheless, there are some disadvantages to adopting in situ MSCs therapy, including difficulties with MSC engraftment into cartilage-deficient regions, the effect of intra-articular inflammation on MSC therapeutic efficacy, and attaining selective chondrogenic MSC differentiation. We created injectable PLGA microspheres (PMs) that were loaded with PDGF-AB and KGN. Metformin was bonded to the surface of microspheres using a Schiff base reaction. The microspheres can recruit intra-articular MSCs and encourage their development into chondrocytes. The microspheres actively modulate the inflammatory joint environment by altering synovial macrophage polarization, thereby supporting MSCs in effective cartilage treatment. To summarize, microspheres hold great potential in the treatment of OA.

Genetic insights into serum cathepsins as diagnostic and therapeutic targets in knee and hip osteoarthritis.

Osteoarthritis (OA) is a chronic disease due to the deterioration of cartilage structure and function, involving the progressive degradation of the cartilage extracellular matrix. Cathepsins, lysosomal cysteine proteases, play pivotal roles in various biological and pathological processes, particularly in protein degradation. Excess cathepsins levels are reported to contribute to the development of OA. However, the causal relationship between the cathepsin family and knee and hip OA remains uncertain. Therefore, this study utilized bidirectional Mendelian Randomization (MR) analyses to explore this causal association. Our results indicated that elevated serum levels of cathepsin O increase the overall risk of knee OA, while increased serum levels of cathepsin H enhance the risk of hip OA. Conversely, the reverse MR analyses did not reveal a reverse causal relationship between them. In summary, OA in different anatomical locations may genetically result from pathological elevations in different serum cathepsin isoforms, which could be utilized as diagnostic and therapeutic targets in clinical practice.

Time-programmed release of curcumin and Zn2+ from multi-layered RSF coating modified PET graft for improvement of graft-host integration.

Artificial graft serves as the primary grafts used in the clinical management of sports-related injuries. Until now, optimizing its graft-host integration remains a great challenge due to the excessive inflammatory response during the inflammatory phase, coupled with an absence of tissue-inductive capacity during the regeneration phase. Here, a multi-layered regenerated silk fibroin (RSF) coating loaded with curcumin (Cur) and Zn2+ on the surface of the PET grafts (Cur@Zn2+@PET) was designed and fabricated for providing time-matched regulation specifically tailored to address issues arising at both inflammatory and regeneration phases, respectively. The release of Cur and Zn2+ from the Cur@Zn2+@PET followed a time-programmed pattern in vitro. Specifically, cellular assays revealed that Cur@Zn2+@PET initially released Cur during the inflammatory phase, thereby markedly inhibit the expression of inflammatory cytokines TNF-a and IL-1ß. Meanwhile, a significant release of Zn2+ was major part during the regeneration phase, serving to induce the osteogenic differentiation of rBMSC. Furthermore, rat model of anterior cruciate ligament reconstruction (ACLR) showed that through time-programmed drug release, Cur@Zn2+@PET could suppress the formation of fibrous interface (FI) caused by inflammatory response, combined with significant new bone (NB) formation during regeneration phase. Consequently, the implementation of the Cur@Zn2+@PET characterized by its time-programmed release patterns hold considerable promise for improving graft-host integration for sports-related injuries.

Effectiveness of low-intensity pulsed ultrasound on osteoarthritis: molecular mechanism and tissue engineering.

Osteoarthritis (OA) is distinguished by pathological alterations in the synovial membrane, articular cartilage, and subchondral bone, resulting in physical symptoms such as pain, deformity, and impaired mobility. Numerous research studies have validated the effectiveness of low-intensity pulsed ultrasound (LIPUS) in OA treatment. The periodic mechanical waves generated by LIPUS can mitigate cellular ischemia and hypoxia, induce vibration and collision, produce notable thermal and non-thermal effects, alter cellular metabolism, expedite tissue repair, improve nutrient delivery, and accelerate the healing process of damaged tissues. The efficacy and specific mechanism of LIPUS is currently under investigation. This review provides an overview of LIPUS's potential role in the treatment of OA, considering various perspectives such as the synovial membrane, cartilage, subchondral bone, and tissue engineering. It aims to facilitate interdisciplinary scientific research and further exploration of LIPUS as a complementary technique to existing methods or surgery. Ongoing research is focused on determining the optimal dosage, frequency, timing, and treatment strategy of LIPUS for OA. Additional research is required to clarify the precise mechanism of action and potential impacts on cellular, animal, and human systems prior to its integration into therapeutic applications.

Consensus statement of Chinese experts on exercise prescription (2023).

Exercise prescriptions play a vital role in the prevention and treatment of chronic diseases. A consensus regarding exercise prescription is important for physical health. The "Consensus statement of Chinese experts on exercise prescription" (hereinafter referred to as "Expert Consensus") divides exercise prescription into two categories: fitness exercise prescription and medical exercise prescription. Traditional Chinese fitness exercises, exercise risk, exercise prescription, and basic precautions for exercise prescription are explained.

Injectable microspheres adhering to the cartilage matrix promote rapid reconstruction of partial-thickness cartilage defects.

An effective treatment for the irregular partial-thickness cartilage defect in the early stages of osteoarthritis (OA) is lacking. Cartilage tissue engineering is effective for treating full-thickness cartilage defects with limited area. In this study, we designed an injectable multifunctional poly(lactic-co-glycolic acid) (PLGA) microsphere to repair partial-thickness cartilage defects. The microsphere was grafted with an E7 peptide after loading the microsphere with kartogenin (KGN) and modifying the outer layer through dopamine self-polymerization. The microsphere could adhere to the cartilage defect, recruit synovial mesenchymal stem cells (SMSCs) in situ, and stimulate their differentiation into chondrocytes after injection into the articular cavity. Through in vivo and in vitro experiments, we demonstrated the ability of multifunctional microspheres to adhere to cartilage matrix, recruit SMSCs, and promote their differentiation into cartilage. Following treatment, the cartilage surface of the model group with partial-thickness cartilage defect showed smooth recovery, and the glycosaminoglycan content remained normal; the untreated control group showed significant progression of OA. The microsphere, a framework for cartilage tissue engineering, promoted the expression of SMSCs involved in cartilage repair while adapting to cell migration and growth. Thus, for treating partial-thickness cartilage defects in OA, this innovative carrier system based on stem cell therapy can potentially improve therapeutic outcomes. STATEMENT OF SIGNIFICANCE: Mesenchymal stem cells (MSCs) therapy is effective in the repair of cartilage injury. However, because of the particularity of partial-thickness cartilage injury, it is difficult to recruit enough seed cells in situ, and there is a lack of suitable scaffolds for cell migration and growth. Here, we developed polydopamine surface-modified PLGA microspheres (PMS) containing KGN and E7 peptides. The adhesion ability of the microspheres is facilitated by the polydopamine layer wrapped in them; thus, the microspheres can adhere to the injured cartilage and recruit MSCs, thereby promoting their differentiation into chondrocytes and accomplishing cartilage repair. The multifunctional microspheres can be used as a safe and potential method to treat partial-thickness cartilage defects in OA.

Surgical management of chronic Achilles tendon rupture: evidence-based guidelines.

BACKGROUND: Chronic Achilles tendon ruptures (CATR) often require surgical intervention to restore function. Despite numerous treatment modalities available, the optimal management strategy remains controversial given the limited high-quality evidence available. This article aims to provide evidence-based guidelines for the surgical management of CATR through a comprehensive systematic review of the available data. The consensus reached by synthesizing the findings will assist clinicians in making informed decisions and improving patient outcomes. METHODS: A group of 9 foot surgeons in three continents was consulted to gather their expertise on guidelines regarding the surgical management of CATR. Following the proposal of 9 clinical topics, a thorough and comprehensive search of relevant literature published since 1980 was conducted for each topic using electronic databases, including PubMed, MEDLINE, and Cochrane Library, to identify relevant studies published until 1 October 2023. All authors collaborated in drafting, discussing, and finalizing the recommendations and statements. The recommendations were then categorized into two grades: grade a (strong) and grade b (weak), following the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) concept. Additionally, feedback from 21 external specialists, who were independent from the authors, was taken into account to further refine and finalize the clinical guidelines. RESULTS: Nine statements and guidelines were completed regarding surgical indications, surgical strategies, and postoperative rehabilitation protocol. CONCLUSION: Based on the findings of the systematic review, this guideline provides recommendations for the surgical management of CATR. We are confident that this guideline will serve as a valuable resource for physicians when making decisions regarding the surgical treatment of patients with CATR.

Corrigendum: Influences of cognitive load on center of pressure trajectory of young male adults with excess weight during gait initiation.

[This corrects the article DOI: 10.3389/fbioe.2023.1297068.].

Optimized OTSU Segmentation Algorithm-Based Temperature Feature Extraction Method for Infrared Images of Electrical Equipment.

Infrared image processing is an effective method for diagnosing faults in electrical equipment, in which target device segmentation and temperature feature extraction are key steps. Target device segmentation separates the device to be diagnosed from the image, while temperature feature extraction analyzes whether the device is overheating and has potential faults. However, the segmentation of infrared images of electrical equipment is slow due to issues such as high computational complexity, and the temperature information extracted lacks accuracy due to the insufficient consideration of the non-linear relationship between the image grayscale and temperature. Therefore, in this study, we propose an optimized maximum between-class variance thresholding method (OTSU) segmentation algorithm based on the Gray Wolf Optimization (GWO) algorithm, which accelerates the segmentation speed by optimizing the threshold determination process using OTSU. The experimental results show that compared to the non-optimized method, the optimized segmentation method increases the threshold calculation time by more than 83.99% while maintaining similar segmentation results. Based on this, to address the issue of insufficient accuracy in temperature feature extraction, we propose a temperature value extraction method for infrared images based on the K-nearest neighbor (KNN) algorithm. The experimental results demonstrate that compared to traditional linear methods, this method achieves a 73.68% improvement in the maximum residual absolute value of the extracted temperature values and a 78.95% improvement in the average residual absolute value.

Antioxidant and anti-inflammatory injectable hydrogel microspheres for in situ treatment of tendinopathy.

Tendinopathy is a common disorder that causes local dysfunction and reduces quality of life. Recent research has indicated that alterations in the inflammatory microenvironment play a vital role in the pathogenesis of tendinopathy. Herein, injectable methacrylate gelatin (GelMA) microspheres (GM) were fabricated and loaded with heparin-dopamine conjugate (HDC) and hepatocyte growth factor (HGF). GM@HDC@HGF were designed to balance the inflammatory microenvironment by inhibiting oxidative stress and inflammation, thereby regulating extracellular matrix (ECM) metabolism and halting tendon degeneration. Combining growth factors with heparin was expected to improve the encapsulation rate and maintain the long-term efficacy of HGF. In addition, the catechol groups on dopamine have adhesion and antioxidant properties, allowing potential attachment at the injured site, and better function synergized with HGF. GM@HDC@HGF injected in situ in rat Achilles tendinopathy (AT) models significantly down-regulated oxidative stress and inflammation, and ameliorated ECM degradation. In conclusion, the multifunctional platform developed presents a promising alternative for the treatment of tendinopathy.

κ-Opioid receptor activation attenuates osteoarthritis synovitis by regulating macrophage polarization through the NF-κB pathway.

Osteoarthritis (OA) is a prevalent and chronic joint disease that affects the aging population, causing pain and disability. Macrophages in synovium are important mediators of synovial inflammatory activity and pathological joint pain. Previous studies have demonstrated the significant involvement of κ-opioid receptor (KOR) in the regulation of pain and inflammation. Our study reveals a significant reduction in synovial KOR expression among patients and mice with OA. Here, we find that KOR activation effectively inhibits the expressions of the LPS-induced-inflammatory cytokines TNF-α and IL-6 by inhibiting macrophage M1 phenotype. Mechanistically, KOR activation effectively suppresses the proinflammatory factor secretion of macrophages by inhibiting the translocation of NF-κB into the nucleus. Our animal experiments reveal that activation of KOR effectively alleviates knee pain and prevents synovitis progression in OA mice. Consistently, KOR administration suppresses the expressions of M1 macrophage markers and the NF-κB pathway in the synovium of the knee. Collectively, our study suggests that targeting KOR may be a viable strategy for treating OA by inhibiting synovitis and improving joint pain in affected patients.

Stem Cells Expansion Vector via Bioadhesive Porous Microspheres for Accelerating Articular Cartilage Regeneration.

Stem cell tissue engineering is a potential treatment for osteoarthritis. However, the number of stem cells that can be delivered, loss of stem cells during injection, and migration ability of stem cells limit applications of traditional stem cell tissue engineering. Herein, kartogenin (KGN)-loaded poly(lactic-co-glycolic acid) (PLGA) porous microspheres is first engineered via emulsification, and then anchored with chitosan through the amidation reaction to develop a new porous microsphere (PLGA-CS@KGN) as a stem cell expansion vector. Following 3D co-culture of the PLGA-CS@KGN carrier with mesenchymal stem cells (MSCs), the delivery system is injected into the capsule cavity in situ. In vivo and in vitro experiments show that PLGA-CS microspheres have a high cell-carrying capacity up to 1 × 104 mm-3 and provide effective protection of MSCs to promote their controlled release in the osteoarthritis microenvironment. Simultaneously, KGN loaded inside the microspheres effectively cooperated with PLGA-CS to induce MSCs to differentiate into chondrocytes. Overall, these findings indicate that PLGA-CS@KGN microspheres held high cell-loading ability, adapt to the migration and expansion of cells, and promote MSCs to express markers associated with cartilage repair. Thus, PLGA-CS@KGN can be used as a potential stem cell carrier for enhancing stem cell therapy in osteoarthritis treatment.

CB2 regulates oxidative stress and osteoclastogenesis through NOX1-dependent signaling pathway in titanium particle-induced osteolysis.

Periprosthetic osteolysis (PPO) induced by wear particles at the interface between the prosthesis and bone is a crucial issue of periprosthetic bone loss and implant failure. After wear and tear, granular material accumulates around the joint prosthesis, causing a chronic inflammatory response, progressive osteoclast activation and eventual loosening of the prosthesis. Although many studies have been conducted to address bone loss after joint replacement surgeries, they have not fully addressed these issues. Focusing on osteoclast activation induced by particles has important theoretical implications. Cannabinoid type II receptor (CB2) is a seven-transmembrane receptor that is predominantly distributed in the human immune system and has been revealed to be highly expressed in bone-associated cells. Previous studies have shown that modulation of CB2 has a positive effect on bone metabolism. However, the exact mechanism has not yet been elucidated. In our experiments, we found that NOX1-mediated ROS accumulation was involved in titanium particle-stimulated osteoclast differentiation. Furthermore, we confirmed that CB2 blockade alleviated titanium particle-stimulated osteoclast activation by inhibiting the NOX1-mediated oxidative stress pathway. In animal experiments, downregulation of CB2 alleviated the occurrence of titanium particle-induced cranial osteolysis by inhibiting osteoclasts and scavenging intracellular ROS. Collectively, our results suggest that CB2 blockade may be an attractive and promising therapeutic scheme for particle-stimulated osteoclast differentiation and preventing PPO.

Exogenous melatonin ameliorates steroid-induced osteonecrosis of the femoral head by modulating ferroptosis through GDF15-mediated signaling.

BACKGROUND: Ferroptosis is an iron-related form of programmed cell death. Accumulating evidence has identified the pathogenic role of ferroptosis in multiple orthopedic disorders. However, the relationship between ferroptosis and SONFH is still unclear. In addition, despite being a common disease in orthopedics, there is still no effective treatment for SONFH. Therefore, clarifying the pathogenic mechanism of SONFH and investigating pharmacologic inhibitors from approved clinical drugs for SONFH is an effective strategy for clinical translation. Melatonin (MT), an endocrine hormone that has become a popular dietary supplement because of its excellent antioxidation, was supplemented from an external source to treat glucocorticoid-induced damage in this study. METHODS: Methylprednisolone, a commonly used glucocorticoid in the clinic, was selected to simulate glucocorticoid-induced injury in the current study. Ferroptosis was observed through the detection of ferroptosis-associated genes, lipid peroxidation and mitochondrial function. Bioinformatics analysis was performed to explore the mechanism of SONFH. In addition, a melatonin receptor antagonist and shGDF15 were applied to block the therapeutic effect of MT to further confirm the mechanism. Finally, cell experiments and the SONFH rat model were used to detect the therapeutic effects of MT. RESULTS: MT alleviated bone loss in SONFH rats by maintaining BMSC activity through suppression of ferroptosis. The results are further verified by the melatonin MT2 receptor antagonist that can block the therapeutic effects of MT. In addition, bioinformatic analysis and subsequent experiments confirmed that growth differentiation factor 15 (GDF15), a stress response cytokine, was downregulated in the process of SONFH. On the contrary, MT treatment increased the expression of GDF15 in bone marrow mesenchymal stem cells. Lastly, rescue experiments performed with shGDF15 confirmed that GDF15 plays a key role in the therapeutic effects of melatonin. CONCLUSIONS: We proposed that MT attenuated SONFH by inhibiting ferroptosis through the regulation of GDF15, and supplementation with exogenous MT might be a promising method for the treatment of SONFH.

MAGL inhibition relieves synovial inflammation and pain via regulating NOX4-Nrf2 redox balance in osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage injury, hyperplasia of bone and inflammatory lesions of synovium. Monoacylglycerol lipase (MAGL), a member of the α/ß hydrolase superfamily, is involved in regulation of injury protection and immune-inflammation response. Autoinflammatory response of the synovium and the release of inflammatory mediators play critical roles in occurrence of early-stage OA. Fibroblast-like synoviocytes (FLSs) are resident mesenchymal cells of the synovial tissue. Considering that MAGL inhibition regulates the inflammatory signaling cascade, it is crucial to ascertain the biological effects and specific mechanisms of MAGL in alleviating inflammatory infiltration of OA FLSs. The aim of this study was to investigate the effect of MAGL on biological function in OA FLSs. Results from in vitro experiments showed that MAGL blockade not only effectively inhibited proliferation, invasion and migration of FLSs, but also downregulated expression of inflammatory-associated proteins. Sequencing results indicated that MAGL inhibition significantly suppressed NOX4-mediated oxidative stress, thus promoting Nrf2 nuclear accumulation and inhibiting generation of intracellular reactive oxygen species (ROS). Attenuation of NOX4 further alleviated redox dysplasia and ultimately improved tumor-like phenotypes, such as abnormal proliferation, migration and migration of FLSs. In vivo results corroborated this finding, with MAGL inhibition found to modulate pain and disease progression in an OA rat model. Collectively, these results indicate that MAGL administration is an ideal therapy treating OA.