Aspirin attenuates the detrimental effects of TNF-α on BMMSC stemness by modulating the YAP-SMAD7 axis.

BACKGROUND: Bone marrow mesenchymal stem cells (BMMSCs) are commonly used for cell transplantation to treat refractory diseases. However, the presence of inflammatory factors, such as tumour necrosis factor-alpha (TNF-α), at the transplantation site severely compromises the stemness of BMMSCs, thereby reducing the therapeutic effect of cell transplantation. Aspirin (AS) is a drug that has been in use for over a century and has a wide range of effects, including the regulation of cell proliferation, multidirectional differentiation, and immunomodulatory properties of stem cells. However, it is still unclear whether AS can delay the damaging effects of TNF-α on BMMSC stemness. METHODS: This study investigated the effects of AS and TNF-α on BMMSC stemness and the molecular mechanisms using colony formation assay, western blot, qRT-PCR, and overexpression or knockdown of YAP and SMAD7. RESULTS: The results demonstrated that TNF-α inhibited cell proliferation, the expression of stemness, osteogenic and chondrogenic differentiation markers of BMMSCs. Treatment with AS was shown to mitigate the TNF-α-induced damage to BMMSC stemness. Mechanistic studies revealed that AS may reverse the damage caused by TNF-α on BMMSC stemness by upregulating YAP and inhibiting the expression of SMAD7. CONCLUSION: AS can attenuate the damaging effects of TNF-α on BMMSC stemness by regulating the YAP-SMAD7 axis. These findings are expected to promote the application of AS to improve the efficacy of stem cell therapy.

Association of peripheral inflammatory indicators with osteoarthritis risk.

Objectives: Numerous studies have established the role of inflammation in osteoarthritis (OA) progression, yet limited research explores the association between systemic inflammatory indicators and pre-diagnosis OA risk. This study aimed to investigate the association between peripheral inflammatory indicators and the risk of OA using data from the UK Biobank. Methods: The study analyzed data from 417,507 participants in the UK Biobank, including neutrophil count, lymphocyte count, monocyte count, platelet count, and C-reactive protein meter. Additionally, derived ratios such as NLR(neutrophils-lymphocytes ratio), PLR(Platelets-lymphocytes ratio), SII(systemic immune-inflammation index), and LMR (lymphocytes-monocytes ratio) were examined. Cox proportional hazards models and restricted cubic spline models were used to assess both linear and nonlinear associations. Results: Over a mean follow-up period of 12.7 years, a total of 49,509 OA events were identified. The findings revealed that CRP (HR:1.06, 95%CI:1.05-1.07), NLR (HR:1.02, 95%CI:1.01-1.03), PLR (HR:1.02, 95%CI:1.01-1.03), and SII (HR:1.03, 95%CI:1.01-1.04) were associated with an increased risk of OA, while LMR (HR:0.97, 95%CI:0.96-0.99) showed a significant negative correlation with OA risk. Subgroup analyses further emphasized that these associations were significant across most of the population. Although neutrophils, lymphocytes, monocytes, and platelets showed a nominal association with the risk of OA, the results were unreliable, especially for specific joint OA. Conclusion: The study provides evidence of a significant association between elevated peripheral inflammatory indicators and OA risk. These findings underscore the importance of low-grade chronic inflammation in OA development. The potential clinical utility of these indicators as early predictors of OA is suggested, warranting further exploration.

Identification of anterior cruciate ligament fibroblasts and their contribution to knee osteoarthritis progression using single-cell analyses.

The mechanical properties of the anterior cruciate ligament (ACL) in the knee have been highlighted, but its role in the regulation of the joint microenvironment remains unclear, especially in the progression of Knee Osteoarthritis (KOA). Here, single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) data were integrated to reveal the transcriptional and epigenomic landscape of ACL in normal and OA states. We identified a novel subpopulation of fibroblasts in ACL, which provides new insights into the role of the ACL in knee homeostasis and disease. Degeneration of the ACL during OA mechanically alters the knee joint homeostasis and influences the microenvironment by regulating inflammatory- and osteogenic-related factors, thereby contributing to the progression of KOA. Additionally, the specific mechanism by which these Inflammation-associated Fibroblasts (IAFs) regulate KOA progression was uncovered, providing new foundation for the development of targeted treatments for KOA.

Nanomaterial-based reactive oxygen species scavengers for osteoarthritis therapy.

Reactive oxygen species (ROS) play distinct but important roles in physiological and pathophysiological processes. Recent studies on osteoarthritis (OA) have suggested that ROS plays a crucial role in its development and progression, serving as key mediators in the degradation of the extracellular matrix, mitochondrial dysfunction, chondrocyte apoptosis, and OA progression. With the continuous development of nanomaterial technology, the ROS-scavenging ability and antioxidant effects of nanomaterials are being explored, with promising results already achieved in OA treatment. However, current research on nanomaterials as ROS scavengers for OA is relatively non-uniform and includes both inorganic and functionalized organic nanomaterials. Although the therapeutic efficacy of nanomaterials has been reported to be conclusive, there is still no uniformity in the timing and potential of their use in clinical practice. This paper reviews the nanomaterials currently used as ROS scavengers for OA treatment, along with their mechanisms of action, with the aim of providing a reference and direction for similar studies, and ultimately promoting the early clinical use of nanomaterials for OA treatment. STATEMENT OF SIGNIFICANCE: Reactive oxygen species (ROS) play an important role in the pathogenesis of osteoarthritis (OA). Nanomaterials serving as promising ROS scavengers have gained increasing attention in recent years. This review provides a comprehensive overview of ROS production and regulation, as well as their role in OA pathogenesis. Furthermore, this review highlights the applications of various types of nanomaterials as ROS scavengers in OA treatment and their mechanisms of action. Finally, the challenges and future prospects of nanomaterial-based ROS scavengers in OA therapy are discussed.

Aspirin reverses inflammatory suppression of chondrogenesis by stabilizing YAP.

Bone marrow mesenchymal stem cells (BMMSCs) transplantation methods are promising candidates for osteoarthritis (OA) treatment. However, inflammatory factors (such as TNF-α) that occur at cell transplantation sites are critical factors that impair the effectiveness of the treatment. Previous studies have shown that aspirin (AS) had a regulatory role in stem cell differentiation. However, little is known about the role of AS on the chondrogenesis of BMMSCs. The purpose of this study is to explore the protective role of AS against the negative effects of TNF-α on BMMSC chondrogenesis. In this study, we investigated the effects of AS and TNF-α on BMMSCs chondrogenesis by performing the Alcian Blue staining, safranin O-fast green staining, haematoxylin and eosin staining, and immunohistochemical staining, as well as real-time RT-PCR and western blot assays. Our results demonstrated that TNF-α inhibited chondrogenic differentiation of BMMSCs by disrupting the balance of cartilage metabolism and promoting oxidative stress in BMMSCs, while AS treatment attenuated these effects. Furthermore, a detailed molecular mechanistic analysis indicated that Yes-associated protein (YAP) played a critical regulatory role in this process. In addition, AS treatment mitigated the progression of cartilage degeneration in a mouse destabilization of the medial meniscus (DMM) model. AS alleviated the inhibitory effect of TNF-α on chondrogenesis of BMMSCs by stabilizing YAP, which may provide new therapeutic strategies for OA treatment.

CircNFIX regulates chondrogenesis and cartilage homeostasis by targeting the miR758-3p/KDM6A axis.

OBJECTIVES: Osteoarthritis (OA) is a degenerative disease causing the progressive destruction of articular cartilage; however, the aetiology has not yet been elucidated. Circular RNAs (circRNAs) are reportedly involved in cartilage degeneration and OA development. In the present study, we identified that circNFIX regulates chondrogenesis and cartilage homeostasis. MATERIALS AND METHODS: Microarray analysis was performed to explore circRNA expression during the chondrogenic differentiation of human adipose-drived stem cells (hADSCs). CircNFIX expression was determined using quantitative reverse transcription-polymerase chain reaction and in situ hybridization. Gain- and loss-of-function assays were performed to validate the role of circNFIX in cartilage homeostasis. RNA pull-down, Argonaute2-RNA immunoprecipitation and luciferase reporter assays were performed to evaluate the interactions among circNFIX, miR758-3p and KDM6A. RESULTS: CircNFIX expression was upregulated in the early and middle stages, whereas downregulated in the late stage of hADSC chondrogenesis. CircNFIX inhibition attenuated hADSC chondrogenesis. CircNFIX was remarkably downregulated in OA samples, circNFIX overexpression protected against chondrocyte degradation and alleviated OA progression in the destabilization of the medial meniscus OA model. Mechanistically, circNFIX acted as a sponge of miR758-3p and played a role in the chondrogenesis and chondrocyte degeneration by targeting the miR-758-3p/KDM6A axis. CONCLUSIONS: Our results revealed a key role of circNFIX in chondrogenesis and cartilage homeostasis, which may provide a potential therapeutic strategy for OA treatment.

Titanium particles induce apoptosis by promoting autophagy in macrophages via the PI3K/Akt signaling pathway.

Chronic inflammation and infection in the tissue surrounding implants after total joint replacement is closely associated with the innate immune response to surgical implants. Wear particles are known to increase apoptosis and impair the innate immunity in macrophages, which can cause immunosuppression around the implants. Excessive autophagy can induce apoptosis. However, the link between autophagy and apoptosis in macrophages during chronic inflammation and infection remains unknown. In this study, we investigated the autophagy and apoptosis induced by titanium particles in RAW264.7 macrophages, and in the interface membrane of patients with late-onset periprosthetic joint infection (PJI). We found that titanium particles stimulated autophagy and apoptosis in macrophages. Inhibition of autophagy significantly reduced titanium particle-induced apoptosis in macrophages, which may be related to the PI3K/Akt signaling pathway. The secretion of inflammatory factors, such as IL-1ß, IL-6, and TNF-α, decreased after inhibition of autophagy in titanium particle-stimulated macrophages, which may be caused by immune dysfunction due to titanium particle-induced autophagy and apoptosis in macrophages. Furthermore, our in vivo mouse calvarial model also showed that autophagy inhibitors lowered the rate of cell apoptosis. Our findings indicate that wear particle-induced apoptosis may be caused by enhanced autophagy in macrophages, which could potentially impair the local innate immunity in periprosthetic tissues and could be a risk factor for PJI. Based on these results, autophagy modulators may act as a new therapeutic option for PJI.