Microgel Encapsulated Mesoporous Silica Nanoparticles for Releasing Wnt16 to Synergistically Treat Temporomandibular Joint Osteoarthritis.

Temporomandibular joint osteoarthritis (TMJOA) is a commonly encountered degenerative joint disease in oral and maxillofacial surgery. Recent studies have shown that the excessive unbalanced activation of Wnt/ß-catenin signaling is connected with the pathogenesis of TMJOA and due to the inability to inhibit the over-activated Wnt pathway, while Wnt16-deficient mice has a more severe Knee OA. However, the efficacy of direct intra-TMJ injection of Wnt16 for the relief of TMJOA is still not directly confirmed. Moreover, small-molecule drugs such as Wnt16 usually exhibit short-lived efficacy and poor treatment adherence. Therefore, in order to obtain a stable release of Wnt16 both in the short and long term, this study fabricates a double-layer slow-release Wnt16 carrier based on mesoporous silica nanospheres (MSNs) encased within hyaluronic acid (HA) hydrogels. The biofunctional hydrogel HA/Wnt16@MSN is analyzed both in vitro and in vivo to evaluate the treatment of TMJOA. As a result, it shows superior pro-cartilage matrix restoration and inhibition of osteoclastogenesis ability, and effectively inhibits the over-activation of the Wnt/ß-catenin pathway. Taken together, biofunctional hydrogel HA/Wnt16@MSN is a promising candidate for the treatment of TMJOA.

Preventing periprosthetic osteolysis in aging populations through lymphatic activation and stem cell-associated secretory phenotype inhibition.

With increases in life expectancy, the number of patients requiring joint replacement therapy and experiencing periprosthetic osteolysis, the most common complication leading to implant failure, is growing or underestimated. In this study, we found that osteolysis progression and osteoclast differentiation in the surface of the skull bone of adult mice were accompanied by significant expansion of lymphatic vessels within bones. Using recombinant VEGF-C protein to activate VEGFR3 and promote proliferation of lymphatic vessels in bone, we counteracted excessive differentiation of osteoclasts and osteolysis caused by titanium alloy particles or inflammatory cytokines LPS/TNF-α. However, this effect was not observed in aged mice because adipogenically differentiated mesenchymal stem cells (MSCs) inhibited the response of lymphatic endothelial cells to agonist proteins. The addition of the JAK inhibitor ruxolitinib restored the response of lymphatic vessels to external stimuli in aged mice to protect against osteolysis progression. These findings suggest that inhibiting SASP secretion by adipogenically differentiated MSCs while activating lymphatic vessels in bone offers a new method to prevent periprosthetic osteolysis during joint replacement follow-up.

Study on pulp metabolism of patients with pulpitis using ultra-performance liquid chromatography coupled with Orbitrap mass spectrometry.

BACKGROUND AND AIMS: Pulpitis, a pulp disease caused by caries, trauma, and other factors, has a high clinical incidence. This study focused on identifying possible metabolic biomarkers of pulpitis cases and analyzing the related metabolic pathways for providing a theoretical foundation to diagnose and prevent pulpitis. MATERIALS AND METHODS: Pulp samples from 20 pulpitis cases together with 20 normal participants were analyzed with a serum metabolomics approach using ultra-high-performance liquid chromatography (UPLC)/Orbitrap mass spectrometry. Moreover, this work carried out multivariate statistical analysis for screening potential biomarkers of pulpitis. RESULTS: Through biomarker analysis and identification, such as partial least squares discrimination analysis, orthogonal partial least squares discriminant analysis model establishment, correlation analysis, and biomarker pathway analysis, 40 biomarkers associated with 20 metabolic pathways were identified, including 20 upregulated and 20 downregulated metabolites. Those major biomarkers included oxoglutaric acid, inosine, citric acid, and PA(14:1(9Z)/PGD1). Among them, oxoglutaric acid and inosine were most significantly downregulated and had the highest correlation with pulpitis. Among these metabolic pathways, GABAergic synapse and alanine, aspartate, and glutamate metabolism were positively correlated with pulpitis. 4. CONCLUSIONS: These biomarkers as well as metabolic pathways may offer the theoretical foundation to understand pulpitis pathogenesis and develop preventive drugs.

Multifunctional Prosthesis Surface: Modification of Titanium with Cinnamaldehyde-Loaded Hierarchical Titanium Dioxide Nanotubes.

Orthopedic prostheses are the ultimate therapeutic solution for various end-stage orthopedic conditions. However, aseptic loosening and pyogenic infections remain as primary complications associated with these devices. In this study, a hierarchical titanium dioxide (TiO2) nanotube drug delivery system loaded with cinnamaldehyde for the surface modification of titanium implants, is constructed. These specially designed dual-layer TiO2 nanotubes enhance material reactivity and provide an extensive drug-loading platform within a short time. The introduction of cinnamaldehyde enhances the bone integration performance of the scaffold (simultaneously promoting bone formation and inhibiting bone resorption), anti-inflammatory capacity, and antibacterial properties. In vitro experiments have demonstrated that this system promoted osteogenesis by upregulating both Wnt/ß-catenin and MAPK signaling pathways. Furthermore, it inhibits osteoclast formation, suppresses macrophage-mediated inflammatory responses, and impedes the proliferation of Staphylococcus aureus and Escherichia coli. In vivo experiments shows that this material enhances bone integration in a rat model of femoral defects. In addition, it effectively enhances the antibacterial and anti-inflammatory properties in a subcutaneous implant in a rat model. This study provides a straightforward and highly effective surface modification strategy for orthopedic Ti implants.

IL13Rα2 as a crucial receptor for Chi3l1 in osteoclast differentiation and bone resorption through the MAPK/AKT pathway.

BACKGROUND: Previous research has revealed that the 18 glycoside hydrolase gene family (GH18) member Chitinase 3-like 1 (Chi3l1) can regulate osteoclast differentiation and bone resorption. However, its downstream receptors and molecular mechanisms during osteoclastogenesis have yet to be elucidated. METHODS: Initially, we conducted a comprehensive investigation to evaluate the effects of recombinant Chi3l1 protein or Chi3l1 siRNA on osteoclast differentiation and the RANKL-induced MAPK/AKT signaling pathways. Moreover, we used immunofluorescence and immunoprecipitation assays to identify IL13Rα2 as the downstream receptor of Chi3l1. Subsequently, we investigated the impact of IL13Rα2 recombinant protein or IL13Rα2-siRNA on osteoclast differentiation and the associated signaling pathways. Finally, we performed in vivo experiments to examine the effect of recombinant IL13Rα2 protein in an LPS-induced mouse model of cranial osteolysis. RESULTS: Our findings highlight that the administration of recombinant Chi3l1 protein increased the formation of osteoclasts and bolstered the expression of several osteoclast-specific genes (TRAP, NFATC1, CTR, CTSK, V-ATPase d2, and Dc-STAMP). Additionally, Chi3l1 significantly promoted the RANKL-induced MAPK (ERK/P38/JNK) and AKT pathway activation, whereas Chi3l1 silencing inhibited this process. Next, using immunofluorescence and co-immunoprecipitation assays, we identified IL13Rα2 as the binding partner of Chi3l1 during osteoclastogenesis. IL13Rα2 recombinant protein or IL13Rα2-siRNA also inhibited osteoclast differentiation, and IL13Rα2-siRNA attenuated the RANKL-induced activation of the MAPK (ERK/P38/JNK) and AKT pathways, similar to the effects observed upon silencing of Chi3l1. Moreover, the promoting effect of recombinant Chi3l1 protein on osteoclastogenesis and the activation of the MAPK and AKT pathways was reversed by IL13Rα2 siRNA. Finally, recombinant LI13Rα2 protein significantly attenuated the LPS-induced cranial osteolysis and the number of osteoclasts in vivo. CONCLUSIONS: Our findings suggested that IL13Rα2 served as a crucial receptor for Chi3l1, enhancing RANKL-induced MAPK and AKT activation to promote osteoclast differentiation. These findings provide valuable insights into the molecular mechanisms of Chi3l1 in osteoclastogenesis, with potential therapeutic implications for osteoclast-related diseases. Video Abstract.

Mechanical overloading leads to chondrocyte degeneration and senescence via Zmpste24-mediated nuclear membrane instability.

Patients with OA and varus knees are subject to abnormal mechanical environment and objective of this study was to investigate the molecular mechanisms underlying chondrocyte senescence caused by mechanical overloading and the role of Zmpste24-mediated nuclear membrane instability in varus knees. Finite element analysis showed that anteromedial region of tibial plateau experienced the most mechanical stress in an osteoarthritis patient with a varus knee. Immunohistochemistry exhibited lower Zmpste24 expression and higher expression of senescence marker p21 in the anteromedial region. Animal experiments and cell-stretch models also demonstrated an inverse relationship between Zmpste24 and mechanically induced senescence. Zmpste24 overexpression rescued cartilage degeneration and senescence in vitro by scavenging ROS. In conclusion, anteromedial tibial plateau is exposed to abnormal stress in varus knees, downregulation of Zmpste24, and nuclear membrane stability may explain increased senescence in this region. Zmpste24 and nuclear membrane stability are potential targets for treating osteoarthritis caused by abnormal alignment.

Dlk2 interacts with Syap1 to activate Akt signaling pathway during osteoclast formation.

Excessive osteoclast formation and bone resorption are related to osteolytic diseases. Delta drosophila homolog-like 2 (Dlk2), a member of the epidermal growth factor (EGF)-like superfamily, reportedly regulates adipocyte differentiation, but its roles in bone homeostasis are unclear. In this study, we demonstrated that Dlk2 deletion in osteoclasts significantly inhibited osteoclast formation in vitro and contributed to a high-bone-mass phenotype in vivo. Importantly, Dlk2 was shown to interact with synapse-associated protein 1 (Syap1), which regulates Akt phosphorylation at Ser473. Dlk2 deletion inhibited Syap1-mediated activation of the AktSer473, ERK1/2 and p38 signaling cascades. Additionally, Dlk2 deficiency exhibits increased bone mass in ovariectomized mice. Our results reveal the important roles of the Dlk2-Syap1 signaling pathway in osteoclast differentiation and osteoclast-related bone disorders.

Associations of periodontitis with risk of all-cause and cause-specific mortality among us adults with chronic kidney disease.

OBJECTIVES: To investigate the associations of periodontitis with risk of all-cause and cause-specific mortality in a nationally representative sample of adults with chronic kidney disease (CKD) in the United States. METHODS: This prospective cohort study included 4,271 individuals aged ≥30 years at baseline with CKD participants in the National Health and Nutrition Examination Survey (NHANES) during 1988-1994, 1999-2004, and 2009-2014. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 and/or urinary albumin/creatinine ratio (uACR) ≥30 mg/g. Multivariate cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and 95 % confidence intervals (CIs) of all-cause and cause-specific mortality in participants with CKD according to periodontitis. The associations of the quartiles of mean clinical attachment loss (CAL) and mean periodontal probing depth (PPD) levels with mortality were examined using the first quartile as the reference group. RESULTS: During a median of 8.67 years of follow-up, 2,146 deaths were documented. After multivariate adjustments, moderate/severe periodontitis was significantly associated with all-cause (HR:1.28; 95 % CI:1.11-1.47; P = 0.001) and cardiovascular disease (CVD)-related mortality (HR:1.44; 95 % CI:1.14-1.81; P = 0.002) in participants with CKD. Compared with the reference group of mean CAL and mean PPD levels, all-cause (CAL: HR, 1.58; 95 % CI, 1.32-1.89, P <0.001; PPD: HR, 1.35, 95 % CI, 1.09-1.67, P = 0.011) and CVD-related mortality (CAL: HR, 1.70, 95 % CI, 1.21-2.40, P = 0.001) were increased for participants in the highest quartile. CONCLUSIONS: This study suggests that moderate/severe periodontitis and high levels of mean CAL and mean PPD are associated with an increased risk of all-cause mortality, and moderate/severe periodontitis and mean CAL associated with CVD-related mortality among adults with CKD in the US. CLINICAL SIGNIFICANCE: This study details the association between periodontitis and the increased risk of all-cause mortality and CVD-related mortality in a large, representative sample of adults with CKD.

Verapamil attenuates intervertebral disc degeneration by suppressing ROS overproduction and pyroptosis via targeting the Nrf2/TXNIP/NLRP3 axis in four-week puncture-induced rat models both in vivo and in vitro.

Low back pain is usually caused by intervertebral disc degeneration (IVDD), during which the involvement of oxidation system imbalance and inflammasome activation cannot be neglected. In this study, we aimed to validate the expression level of TXNIP in IVDD and investigate the function and potential mechanism of action of verapamil. TXNIP is upregulated in the degenerate nucleus pulposus in both humans and rats, as well as in tert-butyl hydroperoxide (TBHP)-stimulated nucleus pulposus cells. Administration of verapamil, a classic clinical drug, mitigated the TBHP-induced overproduction of reactive oxygen species and activation of the NLRP3 inflammasome, thus protecting cells from pyroptosis, apoptosis, and extracellular matrix degradation. The Nrf2/TXNIP/NLRP3 axis plays a major role in verapamail-mediated protection. In vivo, a puncture-induced IVDD rat model was constructed, and we found that verapamil delayed the development of IVDD at both the imaging and histological levels. In summary, our results indicate the potential therapeutic effects and mechanisms of action of verapamil in the treatment of IVDD.

Xl019, a novel JAK inhibitor, suppressed osteoclasts differentiation induced by RANKL through MAPK signaling pathway.

Inbonemetabolism,osteoclastsare the only cellscapableofresorbingbone. Hyperactivity of osteoclasts may lead to osteolytic disease like osteoporosis and arthritis. Although there are several drugs for the treatment of osteolytic diseases, they have limitations and a variety of side effects. An inhibitor of Janus kinase (JAK), XL019, has shown promising results in the treatment of myelofibrosis and other cancers. But whether it can functionally impact osteoclast activity has not been proven. In this study, the effects of XL019 on osteoclastogenesis and the mechanism pathway were investigated in vitro. It was found that XL019 could impair osteoclasts formation, interfere with bone resorption ability and downregulate the osteoclast-specific genes and proteins expression. Furthermore, Western blot and molecular docking studies demonstrated that XL019 inhibited RANKL-induced osteoclastogenesis by suppressing MAPK signaling. A molecular docking analysis explained how XL019 binds to MAPK pathway factors. In addition, titanium particles induced calvarial osteolysis in mice further confirming its beneficial effect on bone homeostasis in vivo. In conclusion, this study demonstrates that Osteoclastactivity canbeeffectivelyinhibitedby XL019viaMAPK signalingpathway,making it a promising alternative pharmacologicaltreatmentfor bone metabolicdisorders.

GLX351322, a Novel NADPH Oxidase 4 Inhibitor, Attenuates TMJ Osteoarthritis by Inhibiting the ROS/MAPK/NF-κB Signaling Pathways.

As a degenerative disease in joints, temporomandibular joint osteoarthritis (TMJOA) is characterized by progressive cartilage degradation, subchondral bone remodeling, and chronic synovitis, severely undermining functions and quality of life in patients. NADPH oxidase 4 (NOX4) contributes to reactive oxygen species (ROS) production and inflammatory pathway activation in osteoarthritis, which has attracted increasing attention in research in recent years. GLX351322 (GLX), a novel NOX4 inhibitor, exerts a protective effect on chondrocytes. However, whether it has a therapeutic effect on ROS production and inflammatory responses in synovial macrophages remains to be evaluated. In this study, we examined the effect of GLX on LPS-induced ROS production and inflammatory responses in vitro and on complete Freund's adjuvant (CFA)-induced TMJ inflammation in vivo. We found that GLX could depress LPS-induced intracellular ROS production and inflammatory response without cytotoxicity by inhibiting the ROS/MAPK/NF-κB signaling pathways. In line with in vitro observations, GLX markedly attenuated the synovial inflammatory reaction in the TMJ, thus protecting the condylar structure from severe damage. Taken together, our results suggest that GLX intervention or NOX4 inhibition is a promising curative strategy for TMJOA and other inflammatory diseases.

Ultrasmall PtAu2 nanoclusters activate endogenous anti-inflammatory and anti-oxidative systems to prevent inflammatory osteolysis.

Rationale: Inflammatory osteolysis, characterized by abundant immune cell infiltration and osteoclast (OC) formation, is a common complication induced by bacterial products and/or wear particles at the bone-prosthesis interface that severely reduces long-term stability after implantation. Molecular nanoclusters are ultrasmall particles with unique physicochemical and biological properties that have great potential as theranostic agents for treating inflammatory diseases. Methods: In this study, heterometallic PtAu2 nanoclusters with sensitive nitric oxide-responsive phosphorescence turn-on characteristics and strong binding interactions with cysteine were designed, making them desirable candidates for the treatment of inflammatory osteolysis. Results: PtAu2 clusters exhibited satisfactory biocompatibility and cellular uptake behavior, with potent anti-inflammatory and anti-OC activities in vitro. In addition, PtAu2 clusters alleviated lipopolysaccharide-induced calvarial osteolysis in vivo and activated nuclear factor erythroid 2-related factor 2 (Nrf2) expression by disrupting its association with Kelch-like ECH-associated protein 1 (Keap1), thereby upregulating the expression of endogenous anti-inflammatory and anti-oxidative products. Conclusion: Through the rational design of novel heterometallic nanoclusters that activate the endogenous anti-inflammatory system, this study provides new insights into the development of multifunctional molecular therapeutic agents for inflammatory osteolysis and other inflammatory diseases.

Osthole Inhibits M1 Macrophage Polarization and Attenuates Osteolysis in a Mouse Skull Model.

Excessive bone resorption due to increased inflammatory factors is a common feature of inflammatory lytic bone diseases. This group of diseases is effectively treated with drugs. In recent years, many studies have reported that traditional Chinese medicine herbs have substantial effects on inflammation, osteoclast differentiation and maturation, and bone destruction. Herein, we investigated the effects of osthole (OST) on lipopolysaccharide- (LPS-) induced macrophage polarization, inflammatory responses, and osteolysis. In vitro, we used immunofluorescence and quantitative real-time polymerase chain reaction assays to confirm whether bone marrow-derived macrophages showed an increased expression of inflammatory factors, such as interleukin-6, iNOS, CCR7, and CD86, in the presence of LPS. However, we found that such expression was suppressed and that the M2 macrophage expression increased in the presence of OST. OST reduced LPS- and RANKL-induced intracellular reactive oxygen species production in the bone marrow-derived macrophages. Further, it potently suppressed osteoclast differentiation and osteoclast-specific gene expression by suppressing the P38/MAPK and NF-κB pathways. Consistent with the in vitro observations, OST greatly ameliorated LPS-induced bone resorption and modulated the ratio of macrophages at the site of osteolysis. Taken together, OST has great potential for use in the management of osteolytic diseases.

Novel Titanium Implant: A 3D Multifunction Architecture with Charge-Trapping and Piezoelectric Self-Stimulation.

Implant-associated infection and inflammation are the main causes of implant failure, causing irreversible damage and significantly increasing clinical risks and economic losses. In this study, a 3D multifunctional architecture is constructed that consisted of hierarchical TiO2 nanotubes (NTs) and electrospun polyvinylidene fluoride nanofiber layers on the surface of a titanium implant. The movement of bacteria through the nanofiber layer is facilitated by its appropriate pore sizes and electrostatic interactions to reach the NT layer where the bacteria are killed by positive charge traps. In contrast, the macrophages tend to adhere to the nanofiber layer. The mechanical interactions between the macrophages and piezoelectric nanofibers generate a self-stimulated electric field that regulated an anti-inflammatory phenotype. This study provides a new method for multifunctional implant materials with antibacterial, piezoelectrically self-stimulated anti-inflammatory, and osteointegration properties that are driven by electrical stimulation.

Balancing the antibacterial and osteogenic effects of double-layer TiO2 nanotubes loaded with silver nanoparticles for the osseointegration of implants.

The improvement of Ag nanoparticles (AgNPs), in particular, loaded titania nanotubes, includes not only the antibacterial effect but also balancing the side effects from the antibacterial effect and osteogenesis properties, which can lead to an increased success rate of implants. Herein, based on the various needs of the graft to inhibit bacteria at different stages in vivo, we used a special osteogenic honeycomb-like "large tube over small tube" double-layered nanotube structure and created ultra-small-sized silver nanoparticles uniformly loaded on the surface and the interior of double-layer nanotubes by an optimized sputter coating method to ensure the time-dependent controllable release of antibacterial Ag ions from grafts and achieve the balance of the antibacterial effect and osteogenesis properties. The release of Ag+ from DNT-Ag8 was determined by inductively coupled plasma spectrometry. The release rate of Ag was slow; it was 30% on the first day and plateaued by the 19th day. Porphyromonas gingivalis adhesion and live bacteria were less abundant on the surface of DNT-Ag8, reaching an antibacterial efficiency of 55.6% in vitro. DNT-Ag8 shows a significantly higher antibacterial effect in a rat model infected with Staphylococcus aureus. An in vitro study demonstrated that DNT-Ag8 had no adverse effects on the adhesion, viability, proliferation, ALP staining, or activity assays of rat BMSCs. In contrast, it increased the expression of osteogenic genes. In vivo, DNT-Ag8 promoted bone-implant osseointegration in a beagle mandibular tooth loss model. This study demonstrated that the uniform loading of small-diameter silver nanoparticles using a honeycomb bilayer nanotube template structure is a promising method for modifying titanium surfaces to improve both bacteriostasis and osseointegration.

Radiologic outcomes of temporomandibular joint disk repositioning by suturing through an open incision in adolescent patients with anterior disk displacement.

PURPOSE: To investigate the efficacy and stability of temporomandibular joint disk repositioning by suturing through an open incision in adolescents with anterior disk displacement (ADD). METHODS: Patients (aged 10-18 years) diagnosed with ADD and operated for disc repositioning between June 2019 and January 2021 were included in this study. Magnetic resonance imaging (MRI) and cephalometric films before and 1 year after surgery were collected from all patients. The surgical success rate was defined as the primary outcome variable. Changes of condylar height, mandibular asymmetry, and retrognathia were defined as the secondary outcome variables. RESULTS: One hundred and four patients (167 joints) with a mean age of 14.6 ± 1.81 years were included in this study. Postoperative MRIs showed that all disks had been repositioned with an overall success rate of 94%. Statistically significant differences were found in the improvement of condylar height (P < .001), mandibular asymmetry (P < .001), and retrognathia (P < .001) after 1 year of follow-up. The relapse rate in patients <15 years (8.57%) was higher than that of patients older than 15 years (4.12%), although this was not statistically significant (P = .387). CONCLUSIONS: For juvenile patients, disk repositioning by suturing through an open incision was an effective treatment. Early surgery can promote condylar regeneration and alleviate maxillofacial deformity in juvenile patients.

ANGPTL4 May Regulate the Crosstalk Between Intervertebral Disc Degeneration and Type 2 Diabetes Mellitus: A Combined Analysis of Bioinformatics and Rat Models.

Introduction: The crosstalk between intervertebral disc degeneration (IVDD) and type 2 diabetes mellitus (T2DM) has been investigated. However, the common mechanism underlying this phenomenon has not been clearly elucidated. This study aimed to explore the shared gene signatures of IVDD and T2DM. Methods: The expression profiles of IVDD (GSE27494) and T2DM (GSE20966) were acquired from the Gene Expression Omnibus database. Five hub genes including ANGPTL4, CCL2, CCN3, THBS2, and INHBA were preliminarily screened. GO (Gene Ontology) enrichment analysis, functional correlation analysis, immune filtration, Transcription factors (TFs)-mRNA-miRNA coregulatory network, and potential drugs prediction were performed following the identification of hub genes. RNA sequencing, in vivo and in vitro experiments on rats were further performed to validate the expression and function of the target gene. Results: Five hub genes (ANGPTL4, CCL2, CCN3, THBS2, and INHBA) were identified. GO analysis demonstrated the regulation of the immune system, extracellular matrix (ECM), and SMAD protein signal transduction. There was a strong correlation between hub genes and different functions, including lipid metabolism, mitochondrial function, and ECM degradation. The immune filtration pattern grouped by disease and the expression of hub genes showed significant changes in the immune cell composition. TFs-mRNA-miRNA co-expression networks were constructed. In addition, pepstatin showed great drug-targeting relevance based on potential drugs prediction of hub genes. ANGPTL4, a gene that mediates the inhibition of lipoprotein lipase activity, was eventually determined after hub gene screening, validation by different datasets, RNA sequencing, and experiments. Discussion: This study screened five hub genes and ANGPTL4 was eventually determined as a potential target for the regulation of the crosstalk in patients with IVDD and T2DM.

CircFOXO3 protects against osteoarthritis by targeting its parental gene FOXO3 and activating PI3K/AKT-mediated autophagy.

Osteoarthritis (OA) is a degenerative joint disorder causing pain and functional disability. Emerging evidence reveals that circular RNAs (circRNAs) play essential roles in OA progression and development. This study aimed to investigate the role of a novel circRNA factor, circFOXO3, in the progression of OA and elucidate its underlying molecular mechanism. The function of circFOXO3 in OA and interaction between circFOXO3 and its downstream mRNA target, forkhead box O3 (FOXO3), were evaluated by western blot (WB), immunofluorescence (IF), RNA immunoprecipitation, reverse transcription-quantitative PCR (RT-qPCR), and fluorescence in situ hybridization (FISH). Upregulation of circFOXO3 and autophagic flux were detected both in vivo and in vitro by WB, transmission electron microscopy (TEM), IF, and immunohistochemistry (IHC). A mouse model of OA was also used to confirm the role of circFOXO3 in OA pathogenesis in vivo. Decreased expression of circFOXO3 in OA cartilage tissues was directly associated with excessive apoptosis and imbalance between anabolic and catabolic factors of the extracellular matrix (ECM). Mechanistically, circFOXO3 functioned in cartilage by targeting its parental gene FOXO3 and activating autophagy. Intra-articular injection of lentivirus-circFOXO3 alleviated OA in the mouse model. In conclusion, our results reveal the key role played by circFOXO3 in OA progression; circFOXO3 overexpression may alleviate apoptosis of chondrocytes and promote anabolism of the ECM via activation of FOXO3 and autophagy, providing a potentially effective novel therapeutic strategy for OA.

Paxlovid accelerates cartilage degeneration and senescence through activating endoplasmic reticulum stress and interfering redox homeostasis.

BACKGROUND: The COVID-19 pandemic has become a huge threat to human health, infecting millions of people worldwide and causing enormous economic losses. Many novel small molecule drugs have been developed to treat patients with COVID-19, including Paxlovid, which block the synthesis of virus-related proteins and replication of viral RNA, respectively. Despite satisfactory clinical trial results, attention is now being paid to the long-term side effects of these antiviral drugs on the musculoskeletal system. To date, no study has reported the possible side effects, such as osteoarthritis, of Paxlovid. This study explored the effects of antiviral drug, Paxlovid, on chondrocyte proliferation and differentiation. METHODS: In this study, both in vitro and in vivo studies were performed to determine the effect of Paxlovid on chondrocyte degeneration and senescence. Furthermore, we explored the possible mechanism behind Paxlovid-induced acceleration of cartilage degeneration using transcriptome sequencing and related inhibitors were adopted to verify the downstream pathways behind such phenomenon. RESULTS: Paxlovid significantly inhibited chondrocyte extracellular matrix protein secretion. Additionally, Paxlovid significantly induced endoplasmic reticulum stress, oxidative stress, and downstream ferroptosis, thus accelerating the senescence and degeneration of chondrocytes. In vivo experiments showed that intraperitoneal injection of Paxlovid for 1 week exacerbated cartilage abrasion and accelerated the development of osteoarthritis in a mouse model. CONCLUSIONS: Paxlovid accelerated cartilage degeneration and osteoarthritis development, potentially by inducing endoplasmic reticulum stress and oxidative stress. Long-term follow-up is needed with special attention to the occurrence and development of osteoarthritis in patients treated with Paxlovid.

[Influence of bilateral coronoidectomy on temporomandibular joint stress distribution after costochondral graft reconstruction: a finite element analysis].

PURPOSE: To explore the effect of bilateral coronoidectomy on stress distribution after reconstruction of temporomandibular joint (TMJ) by costochondral graft. METHODS: Ten groups of models were established to simulate costochondral graft reconstruction with simultaneously different distances (0, 2, 4, 6, 8 mm) of mandibular advancement, with or without coronoidectomy. Force and stress distribution in the rib-cartilage area were analyzed by finite element analysis. RESULTS: In the process of bilateral joint reconstruction with simultaneously mandible advancement ranging from 0 mm to 8 mm, when the coronoid processes were retained, the forward deformation of the cartilage occurred and the shear force decreased in turn, from 113.2 N to 26.7 N on the left side and from 133.7 N to 1.9 N on the right side. When the coronoid processes were removed, the cartilage deformed backward and the shear force increased successively, from 94.6 N to 188.5 N on the left and 70.1 N to 157.7 N on the right. The stress in the neck was obviously concentrated when mandible advanced 8 mm. CONCLUSIONS: Coronoidectomy has an important impact on stress distribution in the TMJ area, and keeping the coronoid process is beneficial to maintain the mechanical balance. Bilateral CCG reconstruction with coronoidectomy for lengthy mandible advancement (≥ 8 mm) may lead to prominent increase in shear force beyond CCG resistance, resulting in a costal-cartilage junction fracture.