Background: While suprascapular nerve (SSN) entrapment is widely recognized as a complication of massive rotator cuff tears (MRCTs), its role as an independent factor affecting tendon healing remains underreported. Additionally, the therapeutic benefit of SSN release in MRCT repair remains controversial. Purpose: To investigate the incidence of SSN entrapment via histological stain and whether SSN release enhances rotator cuff healing in a rat model of delayed MRCT repair. Study Design: Controlled laboratory study. Methods: A chronic MRCT model was established in rats via bilateral transection of the supraspinatus and infraspinatus tendons. After 4 weeks, 5 rats (10 shoulders) were euthanized to assess SSN entrapment incidence via immunofluorescence staining. The remaining 28 rats were randomized into 2 groups: tendon repair (TR) group (n = 14; bilateral tendon reattachment) and tendon repair + nerve release (TR+NR) group (n = 14; same repair with concurrent SSN release). Postoperative evaluations at 4 and 8 weeks included biomechanical testing (maximum load and stiffness) and histological analysis (healing quality, nerve regeneration). Results: SSN entrapments were observed in 7 of 10 shoulders using Neurofilament-200 staining. The TR+NR group demonstrated significantly higher maximum load values at 8 weeks postrepair ( P < .05). Additionally, the TR+NR group achieved significantly superior histological scores compared to the TR group at both 4 and 8 weeks postrepair ( P < .05). Conclusion: SSN release significantly improved rotator cuff healing in rats with chronic MRCTs, as evidenced by enhanced biomechanical strength and histological regeneration. Clinical Relevance: These findings may provide some hints supporting SSN release in patients undergoing MRCT repair.

Intervertebral disc degeneration (IVDD) is a condition that severely impairs the quality of life for patients and is becoming increasingly prominent in aging societies. There is a pressing need to further investigate the mechanisms underlying the initiation and progression of IVDD. Current therapeutic approaches exhibit inconsistent efficacy, highlighting the urgency for the exploration of novel treatment strategies. In this study, we analyzed microarray datasets GSE147383 and GSE124272, downloaded from the Gene Expression Omnibus (GEO) database, which encompass 12 normal samples and 12 samples from patients with lumbar disc herniation. Utilizing R software, STRING, and various databases, we identified differentially expressed genes (DEGs) and constructed a protein-protein interaction (PPI) network. A total of 52 common DEGs were filtered from the datasets. The aim of this study was to investigate the effects of CSF1 knockdown on the inflammatory response and apoptosis in nucleus pulposus cells and to explore the relationship between peripheral blood CSF1 levels and IVDD. Employing cell culture and plasmid transfection techniques, along with the detection of inflammatory markers and analysis of cellular apoptosis, we found that CSF1 knockdown significantly reduced the expression levels of inflammation-related proteins in disc cells, indicating that CSF1 plays a crucial role in the regulation of inflammation and survival in disc cells. Serum testing from human sources also confirmed the significant role of CSF1 in the progression of IVDD. In summary, this study unravels the key role of CSF1 in intervertebral disc degeneration, providing a theoretical foundation for new treatment strategies and laying a solid foundation for future clinical applications. Future research should focus on the clinical application of CSF1 as a biomarker and its differential roles in various pathological states.

Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease. Despite advances in targeted therapies, significant interindividual variability in treatment response and a lack of precise predictive tools limit the achievement of treat‐to‐target goals. This review aims to establish a signaling pathway–biomarker‐targeted therapy coupling paradigm to address unmet clinical needs in precision rheumatology. We systematically reviewed the literature on core pathogenic cascades (JAK/STAT, MAPK, phosphoinositide 4‐kinase–AKT/mechanistic target of rapamycin, spleen tyrosine kinase, Wnt, and Notch) and their crosstalk in RA. We analyzed the direct coupling between pathway dysregulation and specific biomarkers and evaluated emerging therapeutic strategies. We identified a direct mapping between aberrant pathways and biomarkers (eg, interleukin‐6 or C‐reactive protein for JAK/STAT, matrix metalloproteinase 3 for MAPK). Critically, we argue that the failure of most biomarker‐driven trials stems not from the biomarkers themselves but from treating RA as a single entity rather than a spectrum of pathway‐dominant endotypes. Current clinical translation is hindered by heterogeneity and a disconnect between bench research and bedside application. Emerging strategies, including highly selective kinase inhibitors, proteolysis‐targeting chimeras, and nanoparticle‐mediated delivery systems, show promise in overcoming these bottlenecks. Bridging the gap between dysregulated signaling pathways and validated biomarkers is essential for advancing precision medicine in RA. A roadmap for pathway‐guided individualized treatment is proposed.

Objective:To investigate the short-term effectiveness of high tibial osteotomy (HTO) for treatment of middle aged and older populations with varus knee combined with medial meniscus posterior root tear (MMPRT), and to evaluate the biomechanical changes in the knee joint after operation based on finite element analysis. Methods:A retrospective analysis of clinical data was conducted on 35 patients (35 knees) admitted between June 2021 and October 2023, who met the inclusion criteria for varus knee combined with MMPRT. There were 17 males and 18 females with a mean age of 59.2 years (range, 48-65 years). Open wedge HTO was performed to correct the alignment in all patients. X-ray films and MRI were conducted before operation and at 3, 6, and 12 months after operation to assess changes in lower limb alignment and joint structure. And the femorotibial angle, medial proximal tibial angle (MPTA), posterior tibial slope angle (PTSA), weight-bearing line ratio (WBLR), as well as the Lysholm score, Hospital for Special Surgery (HSS) score, and visual analogue scale (VAS) score for pain were compared between pre- and post-operation. Finite element models were reconstructed based on knee CT data from a healthy volunteer to simulate changes in stress distribution at the knee joint before and after HTO, and to analyze postoperative mechanical improvement characteristics. Results:All 35 patients underwent successful operations. Postoperatively, 3 cases of incisional fat liquefaction and 2 cases of mild superficial wound infection occurred; no complication such as deep vein thrombosis of the lower extremities, severe infection, or neurovascular injury was observed. All patients were followed up 12-14 months (mean, 13.0 months). Imaging reexamination revealed that all osteotomies had achieved radiographic union, with no complication such as osteotomy loss, significant collapse, or plate fracture. At 12 months after operation, the femorotibial angle, MPTA, WBLR, and PTSA were all significantly higher than preoperative levels ( P<0.05). Compared with preoperative values, the Lysholm score and HSS score gradually increased, while the VAS score decreased at 3, 6, and 12 months, with significant differences between different time points ( P<0.05). Finite element analysis showed that the stress distribution in the medial and lateral compartments of the knee joint tended toward equilibrium after HTO. Medial cartilage contact stress decreased by approximately 40% compared to preoperative levels, and stress concentration in the medial meniscus was significantly reduced. Conclusion:HTO can significantly alleviate knee pain in middle aged and older populations with varus knee combined with MMPRT, improve the distribution of knee joint forces, and promote the recovery of joint function.

Age-related diseases are often linked to chronic inflammation. Senescent cells secrete inflammatory cytokines, chemokines and matrix metalloproteinases, collectively referred to as the senescence-associated secretory phenotype (SASP). The current study discovered that aging leads to the accumulation of senescent tendon stem/ progenitor cells (TSPCs) in tendon tissue, resulting in the development of a SASP. Conditioned medium from aged TSPCs induced cellular inflammation in young TSPCs. In addition, we found that Canopy homolog 2 (CNPY2) expression is reduced during tendon aging. CNPY2 deficiency causes TSPCs senescence and SASP. Our findings showed that the NF-kappa B signaling pathway is activated in CNPY2 knockdown TSPCs, pharmacological inhibition of NF-kappa B signaling pathway with BMS-345541 attenuated SASP of senescent TSPCs, which indicated that CNPY2 regulates TSPCs SASP might through NF-kappa B signaling pathway. Our findings suggested that CNPY2 plays an important role in TSPCs senescence and SASP, CNPY2 could be a promising target for age-related tendon disorders.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by progressive joint degradation, with mitochondrial dysfunction significantly contributing to its pathogenesis. Despite extensive research into therapeutic strategies, successfully addressing mitochondrial dysfunction in RA poses a significant challenge. This paper presents an innovative functionalization method, deploying hydrocaffeic acid-modified chitosan, in conjunction with the selective calcium chelator ethylene glycol bis(β-aminoethyl ether)-N,N,N’,N’-tetraacetic acid (EGTA), and incorporating stromal cell-derived factor 1 alpha (SDF-1α). In vitro, this functionalized hydrogel exhibited a significant decrease in intracellular reactive oxygen species (ROS) levels, stabilization of mitochondrial membrane potential, mitigation of calcium overload, inhibition of mitochondrial dysfunction-induced cellular senescence, and a reduction in the release of senescence-associated secretory phenotype components. In vivo, this hydrogel effectively modulated immune responses and aided cartilage repair in a collagen-induced arthritis rat model. From a mechanistic perspective, high-throughput sequencing suggests that the therapeutic efficacy of this hydrogel may be associated with its ability to modulate mitochondrial function and inflammatory pathways. In summary, the hydrocaffeic acid- and EGTA-based functionalization strategy provides an innovative and straightforward process for integrating multiple functionalities into a single delivery platform, demonstrating the potential for tissue regeneration applications extending beyond RA.

Cognitive dysfunction is a major feature of brain aging. However, there is no effective treatment for brain aging. Aerobic exercise is a non-side-effective intervention that is effective in neurodegenerative diseases such as aging. The aim of this study was to explore the potential of treadmill exercise in preventing oxidative stress-induced brain aging and neurodegenerative diseases by investigating the effects of treadmill exercise and its mechanisms in D-galactose-induced mice. The results showed that D-galactose-induced C57BL/6 mice exhibited cognitive deficits, myelin deficits, and increased neuronal apoptosis. Additionally, we observed significantly elevated average optical density values of IBA-1, a microglia-specific marker, in the senescent group. These were effectively mitigated following the treadmill exercise. The study also found that treadmill exercise increased the expression of Silent Information Regulator 1 (SIRT1) and Peroxisome proliferator-activated receptor γ (PPARγ) proteins, while decreasing the expression of p-NFKB. Immunofluorescence double-labeling further validated that SIRT1 and PPARγ co-localized and that treadmill exercise contributed to increased SIRT1 and PPARγ overlapping fluorescence intensity. Treadmill exercise decreased the expression of IL-1β and iNOS, and decreased the number of TUNEL-positive cells and the expression of the apoptosis executor caspase3. The results suggest that aerobic exercise has the potential to ameliorate the cognitive deficits observed in D-galactose mice by modulating the SIRT1/PPARγ signaling pathway to impede microglia-induced neuroinflammation and reduce apoptosis. Treadmill exercise appears to have the potential to be an effective treatment for attenuating microglia inflammation-induced brain aging and neurodegenerative diseases.

Background:Genetic factors are key determinants of vulnerability to rheumatoid arthritis (RA), a systemic inflammatory disease that causes inflammation, pain, swelling, and destruction of the joints. Expression quantitative trait loci (eQTLs) have been shown to detect novel disease-risk loci in previous studies. In this paper, we identified new susceptibility genes in RA and investigated their underlying mechanisms using integrated Mendelian randomization (MR) analysis. Methods:Two-sample MR analyses were used to determine the causative links among eQTLs, metabolites, and RA risk. The study was conducted between January 2023 and June 2024. Synovial tissue samples were collected from patients undergoing joint surgery at the Affiliated Hospital of Nantong University. Functional validation of the candidate gene vesicular overexpressed in cancer pro-survival protein 1 (VOPP1) was performed in vitro using rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs), and in vivo in a collagen-induced arthritis (CIA) rat model. Expression levels of VOPP1 were evaluated by quantitative real-time PCR and Western blot. Additional assays assessed cell proliferation, inflammatory cytokine expression, and activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Results:Our findings offer the first evidence that RA risk is increased by the VOPP1 eQTL. Furthermore, we discovered that the VOPP1 eQTL positively modulates the X-23,587 metabolite's levels, and raising this metabolite may make RA risk worse. Moreover, we demonstrate that VOPP1 is highly expressed in RA synovial tissues and RA-FLSs. VOPP1 stimulates the proliferation of RA-FLSs and the inflammatory response through the p38 MAPK signaling pathway according to functional experiments. We showed that VOPP1 knockdown reduced articular damage and synovial inflammation in vivo using a CIA rat model. Conclusion:This study identifies VOPP1 as a novel gene associated with rheumatoid arthritis susceptibility. VOPP1 may contribute to disease progression by elevating X-23,587 metabolite levels and activating the p38 MAPK signaling pathway.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by sustained synovial inflammation and the gradual destruction of joint structures. Although conventional T cells have historically been viewed as central to RA pathogenesis, increasing attention has recently focused on unconventional T cell subsets, such as natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells, and gamma delta T (γδ T) cells. Functioning as a bridge between innate and adaptive immunity, these cells contribute to RA immunopathogenesis by producing cytokines, exerting cytotoxic effects, and interacting with various immune and stromal cells. This review offers a comprehensive analysis of the immunological characteristics and pathogenic roles of unconventional T cell subsets in RA. NKT, MAIT, and γδ T cells contribute to the amplification of inflammatory responses and joint tissue destruction through diverse mechanisms, exhibiting unique tissue tropism and functional plasticity. Recently, novel therapeutic strategies have been developed to target these subsets, including modulation of antigen presentation pathways, inhibition of pro-inflammatory signaling cascades, and reprogramming of cellular functionalities. Advancements in single-cell omics and spatial immune profiling have facilitated the precise identification and characterization of pathogenic unconventional T cell subsets in the RA synovium, thereby paving the way for personalized immunotherapeutic approaches.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by chronic inflammation of the synovium and progressive joint damage. Fibroblast-like synoviocytes (FLSs) exhibit excessive proliferative and aggressive phenotypes and play a major role in the pathophysiology of RA. Previous studies have confirmed the pathologic role of L-selectin in cell adhesion and migration. In rheumatoid arthritis models, L-selectin regulates leukocyte homing, which leads to joint inflammation. Moreover, in L-selectin knockout mice, there is a reduction in joint inflammation. However, the associations of L-selectin with FLSs in RA remain unclear. This study aims to reveal the effect of L-selectin on RA-FLSs and to investigate the molecular mechanism of L-selectin in RA. Our findings indicated that L-selectin was significantly expressed in RA synovial tissues and RA-FLSs. L-selectin silencing reduced RA-FLSs migration and invasion and attenuated the secretion of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in vitro. Moreover, investigations into mechanisms revealed that L-selectin activated the nuclear factor kappa-B (NF-κB) signaling pathway while blocking this signaling pathway could compromise the effects of L-selectin. Finally, in vivo experiments with a collagen-induced arthritis rat model revealed that silencing L-selectin alleviated inflammatory infiltration of the synovium and cartilage destruction, and validated the NF-κB signaling pathways findings observed in vitro. In summary, we show that L-selectin enhances the migration and invasion of RA-FLSs through the activation of NF-κB signaling pathways, ultimately worsening the progression of RA.

INTRODUCTION:The presence of a posterior malleolar (PM) fragment has a negative prognostic impact in ankle fractures. Percutaneous anterior to posterior screw fixation has been advocated for the treatment of ankle fractures involving the posterior malleolus and satisfactory results were demonstrated in several studies. The aim of this retrospective study was to evaluate the clinical effect of percutaneous anterior to posterior screw fixation via lateral malleolus incision window approach (APSF-LMA) for the treatment of posterior malleolus fracture (PMF) and present outcomes of patients with type 4 of Bartoníček-Rammelt classification in comparison to using the dorsiflexion ankle anterior posterior screw fixation (APSF-DA) and posterior plate fixation through posterolateral approach (PPF-PLA). METHODS:We retrospectively reviewed the clinical outcomes of 58 patients with ankle fractures involving Bartoníček-Rammelt type 4 PMF from January 2019 to December 2023. Comparisons were conducted between the groups regarding operative time, union time, the Olerud-Molander Ankle Score (OMAS), the EuroQol-5 Dimensions (EQ-5D), the American Orthopedic Foot and Ankle Society score (AOFAS), Kellgren-Lawrence (KL) osteoarthritis classification and clinical findings. RESULTS:The demographic characteristics were comparable between the groups. Fewer operative time was performed in the APSF-LMA (79(75-84.5) mins) and APSF-DA (78(70-85) mins) groups than in the PPF-PLA group (105(98-112) mins; P < 0.0001). When compared with the other two approaches, the APSF-LMA approach was associated with higher AOFAS scores (P < 0.05) and lower grade of KL (P < 0.0001) at the last follow-up. No significant intergroup differences were detected in the incidence of complications (P > 0.999), OMAS scores (P = 0.921) and EQ-5D (P = 0.806). Radiological and clinical findings demonstrated that fixation of the distal fibula (P = 0.727), the time of bony union and postoperative angulation (P = 0.846) were similar between the groups. CONCLUSIONS:The APSF-LMA approach can serve as a safe and effective option for posterior malleolus fractures, as it offers favorable outcomes in ankle operation time and ankle functional recovery in the early postoperative period and is equivalent to the other two approaches in terms of the incidence of complications, fracture healing and postoperative angulation for patients with posterior malleolus fractures.

Rheumatoid arthritis (RA) is a chronic autoimmune disease with an unknown etiology. RA cannot be fully cured and requires lengthy treatment, imposing a significant burden on both individuals and society. Due to the lack of specific drugs available for treating RA, exploring a key new therapeutic target for RA is currently an important task. Activated fibroblast-like synoviocytes (FLSs) play a crucial role in the progression of RA, which release interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α resulting in abnormal inflammatory reaction in the synovium. A previous study has highlighted the correlation of m6A reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) with inflammation-related diseases in human. However, the role of IGF2BP2 in the inflammatory reaction of FLSs during RA progression has not been assessed. In this study, IGF2BP2 expression was decreased in the synovial tissues of RA patients and collagen-induced arthritis (CIA) rats. Intra-articular injection of an adeno-associated virus (AAV) vector overexpressing IGF2BP2 relieved paw swelling, synovial hyperplasia and cartilage destruction in CIA rats. IGF2BP2 overexpression also inhibited lipopolysaccharide (LPS)-mediated RA fibroblast-like synoviocytes (RA-FLSs) migration and invasion accompanied by a decreased level of inflammatory factors in vitro. Conversely, IGF2BP2 suppression promoted RA-FLSs migration and invasion with an elevated level of inflammatory factors in vitro. The sequencing result showed that glutathione S-transferase Mu 5 (GSTM5), a key antioxidant gene, was the target mRNA of IGF2BP2. Further experiments demonstrated that IGF2BP2 strengthened the stability of GSTM5 mRNA, leading to weakened inflammatory reaction and reduced expression of matrix metalloproteinase 9 and 13 (MMP9, MMP13). Therefore, IGF2BP2-GSTM5 axis may represent a potential therapeutic target for RA treatment.

Background: In the natural course of osteonecrosis of the femoral head, sclerotic changes at the boundary of necrotic lesion gradually occur until femoral head collapse. This study aims to examine the effects of bone mineral density at the lateral boundary of necrotic lesion on a subsequent femoral head collapse. Methods: We developed patient -specific finite element models of 9 hips with subsequent collapse and 10 hips without subsequent collapse. Cubic regions of interest were selected at both subchondral areas of the lateral boundary and the adjacent necrotic lesion. Bone mineral density values of the regions of interest were quantitatively measured, and a ratio of bone mineral density values (lateral boundary/necrotic lesion) was calculated. Stress values at the lateral boundary were also evaluated. Findings: The ratio of bone mineral density values was significantly higher in hips with subsequent collapse than that without subsequent collapse (p = 0.0016). The median equivalent stress and shear stress were significantly higher in hips with subsequent collapse than that without subsequent collapse (p = 0.0071, and p = 0.0143, respectively). The ratio of bone mineral density values showed a promising value in predicting the occurrence of subsequent femoral head collapse (AUC = 0.97). Interpretation: Our results indicated that bone mineral density value at the lateral boundary of necrotic lesion may be associated with the occurrence of subsequent femoral head collapse in pre -collapse stage osteonecrosis of the femoral head.

Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease with a complex pathogenesis that has not yet been fully elucidated, and T-cell pyroptosis is an important pathogenetic factor in RA. This study aimed to investigate the role of endoplasmic reticulum aminopeptidase 2 (ERAP2) in the pyroptosis of CD4+ T cells in RA and the specific molecular mechanism. Peripheral venous blood was collected from human subjects, and CD4+ T cells were isolated and activated to measure the level of pyroptosis and ERAP2 expression. Pyroptosis levels were assessed using immunofluorescence, flow cytometry, qRT-PCR, and Western blotting. Changes in pyroptosis levels were observed upon knockdown or overexpression of ERAP2. To detect activated Caspase-1 in tissues, chimeric mice were engrafted with human synovial tissue and reconstituted with human CD4+ T cells. CD4 + T cells were treated with GLI1 antagonists and SMO receptor agonists to detect changes in pyroptosis levels. CD4+ T cell levels undergoing pyroptosis were found to be elevated in the blood and synovium of RA patients. The gene and protein expression of ERAP2 were significantly higher in CD4+ T cells from RA patients. Deletion of ERAP2 suppressed pyroptosis of these cells, attenuated the activation of Caspase-1 in tissue T cells, and reduced tissue inflammatory responses. Reciprocally, overexpression of ERAP2 triggered inflammasome assembly, activated Caspase-1, and induced pyroptosis in CD4+ T cells. Mechanistically, ERAP2 inhibits the Hedgehog signaling pathway and upregulates the expression of nucleotide-binding oligomerization segment-like receptor family 3(NLRP3), cleaved Caspase-1, and Gasdermin D to promote pyroptosis in CD4+ T cells. Taken together, our results identify a novel mechanism by which ERAP2 regulates RA development and document the effect of the ERAP2/Hedgehog signaling axis on pyroptosis of CD4+ T cells from RA patients.

Long-term fluorescence monitoring of subcellular organelles is crucial for cellular physiology and pathology studies. Lipid droplets (LDs) are increasingly recognized for their involvement in various biological processes, to influence disease development through diverse behaviors However, existing LD probes face challenges in achieving high targeting and long-term monitoring due to poor photostability and long-term phototoxicity. Carbon quantum dots (CQDs) have gained prominence due to their exceptional fluorescence properties, but their prevalent blue excitation wavelength presents difficulties for long-term imaging. Herein, we synthesized red-emissive carbon quantum dot (R-CQDs) with superior photobleaching resistance and red-emission, thus enabling harmlessly fluorescence monitoring of cells longer than 3 h. In addition, R-CQD exhibits suitable amphiphilicity and remarkable solvatochromic effect, allowing rapid targeting to LDs for immediate imaging without cumbersome washing steps. Hence, R-CQD shows high performance for extended observation of dynamic LD behavior in various biological processes, which is confirmed by documenting the course of LDs during starvation as well as lipotoxicity. Compared to commercial probes, R-CQD extends live cell imaging time by at least 9-fold, facilitating the study of LD behavioral characteristics under diverse physiological or pathological conditions. This work provides a reliable fluorescence tool for tracking intercellular microenvironment dynamically thus to understand the divers biological or disease mechanism.

Cartilage defects in the knee are often associated with the progression of degenerative osteoarthritis (OA), and cartilage repair is a useful strategy for managing this disease. However, cartilage repair is challenging because of the unique environment within the tissue. Recently, stem cell-based therapies have shed new light on this issue. In this study, we prepared exosomes (EXOs) from cartilage stem/progenitor cells (CSPCs) and found that treatment with EXOs increased the viability, migration, and proliferation of cultured primary chondrocytes. In a subacute OA rat model, the application of EXOs facilitated cartilage regeneration as evidenced by histological staining. Exosomal protein analysis together with bioinformatics suggested that cyclin-dependent kinase 9 (CDK9) is a key factor for chondrocyte growth and migration. Functional studies confirmed this prediction, that is, inhibiting CDK9 reduced the beneficial effects induced by EXOs in primary chondrocytes; while overexpression of CDK9 recapitulated the EXOs-induced phenotypes. RNA-Seq data showed that a set of genes involved in cell growth and migration were up-regulated by EXOs in chondrocytes. These changes could be partially reproduced by CDK9 overexpression. Overall, our data suggest that EXOs derived from primary CSPCs hold great therapeutic potential for treating cartilage defect-associated disorders such as degenerative OA, and that CDK9 is a key factor in this process.

Pyroptosis, an inflammatory form of programmed cell death, is linked to the pathology of rheumatoid arthritis (RA). Here, we investigated the molecular mechanism underlying pyroptosis in T cells isolated from patients with RA. Compared with healthy individuals, patients with RA had more pyroptotic CD4+ T cells in blood and synovia, which correlated with clinical measures of disease activity. Moreover, the mRNA expression and protein abundance of arachidonate 5-lipoxygenase (ALOX5), which converts arachidonic acid to leukotriene A4 (LTA4), were increased in CD4+ T cells from patients with RA and, among patients with RA, were lowest in those in clinical remission. Knockdown or pharmacological inhibition of ALOX5 suppressed CD4+ T cell pyroptosis and improved symptoms in two rodent models of RA. Mechanistically, the increase in ALOX5 activity in RA CD4+ T cells enhanced the production of the LTA4 derivative LTB4, which stimulated Ca2+ influx through ORAI3 channels, leading to the activation of NLRP3 inflammasomes and pyroptosis. Our findings reveal a role for ALOX5 in RA and provide a molecular basis for further exploring the clinical utility of ALOX5 inhibition in RA and for using ALOX5 as a biomarker to distinguish active disease and remission in RA.

Tendon stem/progenitor cells (TSPCs) are crucial for tendon repair, regeneration, and homeostasis. Dysfunction of TSPCs, due to aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, contributes to tendinopathy. Unfortunately, the effectiveness of conventional subcutaneous injection targeting at suppressing JAK/STAT signaling pathway is limited due to the passive diffusion of drugs away from the injury site. Herein, a novel poly-gamma-glutamic acid (γ-PGA) dual-barb microneedle (MN) path loaded with TSPCs-derived nanovesicles (NVs) containing JAK/STAT inhibitor WP1066 (MN-WP1066-NVs) for tendinopathy treatment is designed. The dual-barb design of the MN ensures firm adhesion to the skin, allowing for sustained and prolonged release of WP1066-NVs, facilitating enhanced TSPCs self-renewal, migration, and stemness in tendinopathy. In vitro and in vivo experiments demonstrate that the degradation of γ-PGA patch tips facilitates the gradual release of WP1066-NVs at the lesion site. This release alleviates inflammation, suppresses extracellular matrix degradation, and restores normal tendon histological structure by inhibiting the JAK/STAT pathway. These findings suggest that the multifunctional dual-barb MN patch offers a novel and effective therapeutic strategy for tendinopathy treatment.

Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease. Over-activation of fibroblast-like synoviocytes is responsible for the hyperplasia of synovium and destruction of cartilage and bone and pyroptosis of FLS plays a key role in those pathological processes during RA. This study investigated the detailed mechanisms that SMAD2 regulates the pyroptosis of FLS and secretion of inflammatory factors in rheumatoid arthritis. We collected synovial tissues of RA patients and FLS-RA and cultured FLS for detection of expression of SMAD2. ASC, NLRP3, cleaved-caspase-1, and GSDMD-N were detected by Western blot after overexpression of SMAD2. Besides, flow cytometry, electron microscope, ELISA, HE staining, and Safranin O staining were performed to further demonstrate that SMAD2 can affect the pyroptosis of FLS-RA. The expression of SMAD2 was down-regulated in synovial tissues of RA patients and FLS-RA. Overexpression of SMAD2 can inhibit the expression of ASC, NLRP3, cleaved-caspase-1, and GSDMD-N. Flow cytometry and electron microscope further demonstrated that SMAD2 attenuated pyroptosis of FLS-RA. In addition, overexpression of SMAD2 also inhibited inflammatory factors such as IL-1β, IL-18, IL-6, and IL-8 secretion and release of LDH. Besides, overexpression of SMAD2 can reverse the decrease of p-SMAD2 and TGF-TGF-β induced by nigericin. In vivo experiments on CIA rats further demonstrated that overexpression of SMAD2 by local intra-articular injection of LV-SMAD2 can effectively alleviate joint redness, swelling, and destruction of cartilage and bones. SMAD2 inhibited FLS-RA pyroptosis by down-regulating of NLRP3 inflammasomes (NLRP3, ASC, and caspase-1 complex) and eased the secretion of inflammatory factors via the TGF-β signaling pathway, thereby improving the symptom of RA. We hope that this study may provide a new research idea for RA and a potential target for the treatment of RA.

目的:探讨 3DBody解剖软件联合关节镜训练模拟器在运动医学临床教学中的应用效果.方法:选取骨科研究生40 例,随机分为对照组和观察组各 20例.对照组采用关节镜训练模拟器实操教学,观察组在对照组教学的基础上利用3DBody解剖软件重点讲解关节镜手术相关解剖知识.比较两组操作考核、理论考试及教学满意度.结果:观察组操作考核成绩 93.30±4.35 分、理论考试成绩 87.95±5.68 分,分别高于对照组的 88.15±5.22 分和 83.50±6.76 分,差异均有统计学意义(P＜0.05).观察组教学总满意度100%,高于对照组的 75.0%,差异有统计学意义(P＜0.05).结论:3DBody解剖软件联合关节镜训练模拟器可显著提高运动医学临床教学效果.