Osteoarthritis (OA), a debilitating and progressive joint disease, presents major therapeutic challenges due to chondrocyte ferroptosis, chronic synovial inflammation, and the pharmacokinetic limitations of conventional intra-articular therapies, such as rapid clearance and poor retention. To overcome these barriers, we developed a dual-functional intra-articular delivery platform composed of a gelatin-hyaluronic acid hydrogel encapsulating fenofibrate-loaded, cartilage-targeting nanoparticles (FNPs-GelHA hydrogel). This system synergistically inhibits OA progression by simultaneously suppressing chondrocyte ferroptosis and modulating the inflammatory joint microenvironment. In vitro studies revealed that FNPs-GelHA hydrogel markedly attenuates chondrocyte ferroptosis, inflammation, oxidative stress, and lipid peroxidation. Furthermore, this system effectively reprograms macrophage polarization by suppressing pro-inflammatory M1 phenotypes and promoting reparative M2 phenotypes, thereby contributing to immunomodulation and cartilage repair. In addition, in vivo experiments demonstrated prolonged joint retention of this system and significant therapeutic efficacy in delaying OA progression. By integrating targeted drug delivery, ferroptosis inhibition, and immune microenvironment remodeling, this composite hydrogel-nanoparticle platform offers a synergistic and promising strategy for OA treatment.

Abstract Chronic bone and joint diseases severely affect the functional status of bone, cartilage, and soft tissues, thus leading to pain and dysfunction in the affected areas. Patients with these diseases can be treated by conservative methods such as oral medications in the early stages, while surgical interventions are commonly required for those in the advanced stage. As conventional anti-osteoporosis (OP) drugs, anti-inflammatory drugs, painkillers, and immunomodulators may induce side effects and drug resistance in the treatment process, it is necessary to explore new therapeutic drugs for the adjuvant treatment of chronic bone and joint diseases at an early or advanced stage. Epimedium is an herbal medicine in traditional Chinese medicine (TCM) and has been used for more than 2,000 years. As the main active ingredient in this herbal medicine, icariin (ICA) is effective in the treatment of chronic bone and joint diseases. This ingredient can be involved in the pathophysiological process of these diseases via modulating the osteogenic and chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), inhibiting osteoclastogenesis, resisting inflammation, protecting the extracellular matrix (ECM), regulating oxidative stress (OS), and participating in immunomodulation. In this study, the role of Epimedium in the prevention and treatment of chronic bone and joint diseases was systematically reviewed. The results demonstrated that Epimedium can be used as a complementary and alternative medicine for the treatment of chronic bone and joint diseases. In this paper, the mechanism of action and potential application of Epimedium in the prevention and treatment of chronic bone and joint diseases were summarized. These findings may lay a foundation for the further development and clinical application of Epimedium as a medicinal food source.

Sarcomas are aggressive, immunologically cold tumors with limited benefit from immune-checkpoint blockade (ICB). Through integrated multi-omics, functional, and clinical analyses, we identify pyruvate dehydrogenase alpha 1 (PDHA1)-a cuproptosis-linked metabolic gene-as a driver of sarcoma progression and immune evasion. PDHA1 is consistently overexpressed across TCGA/GEO/ICGC cohorts and associates with poor prognosis, stromal activation, and reduced immune scores; single-cell RNA-seq of the immune compartment shows PDHA1 expression across multiple immune populations, with higher levels in T cells and monocytes/dendritic cells. PDHA1 knockdown diminishes proliferation, invasion, clonogenicity, and PD-L1 levels while increasing apoptosis. Mechanistically, PDHA1 elevates E2F1, which binds and transactivates the PD-L1 promoter; rescue assays confirm E2F1-dependent PD-L1 induction. Copper chelation with tetrathiomolybdate lowers lipoylated DLAT and suppresses the PDHA1-E2F1-PD-L1 axis. In 3D spheroids, xenografts, and multiplex immunofluorescence, high PDHA1 aligns with larger tumors, higher Ki-67/BCL-2, lower cleaved caspase-3, increased PD-L1, and reduced CD8⁺ T-cell infiltration. PDHA1 hypomethylation correlates with worse survival. PDHA1 status also modulates sensitivity to phenformin and the E2F1 pathway inhibitor NSC-207895. Collectively, PDHA1 orchestrates a cuproptosis-associated E2F1-PD-L1 program that promotes immune exclusion yet predicts ICB responsiveness, supporting PDHA1 as a clinically actionable biomarker and metabolic-immunologic target in sarcoma.

Sarcomas are a heterogeneous group of mesenchymal malignancies with diverse histological subtypes, limited treatment options, and generally poor outcomes in advanced disease. EXT2, a glycosyltransferase involved in heparan sulfate biosynthesis, has been implicated in tumor–microenvironment interactions, but its role in sarcoma progression and immune regulation remains incompletely understood. We integrated transcriptomic, epigenomic, and immune landscape analyses across public sarcoma datasets and clinical specimens to investigate the clinical and biological relevance of EXT2. Functional effects of EXT2 were assessed using in vitro assays, in vivo tumor models, and CD8+ T-cell co-culture systems. Single-cell RNA sequencing data were analyzed to localize EXT2 expression within the tumor microenvironment. EXT2 was consistently upregulated in sarcoma tissues and associated with unfavorable survival outcomes, with particularly consistent evidence in osteosarcoma cohorts. EXT2 silencing suppressed tumor cell proliferation, migration, invasion, and in vivo growth, accompanied by reduced AKT phosphorylation, c-Myc expression, and PD-L1 levels. EXT2-high tumors exhibited features of an immune-excluded microenvironment, including reduced CD8+ T-cell infiltration and enrichment of cancer-associated fibroblasts and M2-like macrophages. Although EXT2 expression was associated with higher tumor mutational burden and microsatellite instability, EXT2-high tumors showed predicted immune exclusion and reduced responsiveness to immune checkpoint blockade. Single-cell analyses localized EXT2 predominantly to stromal and endothelial compartments. These findings identify EXT2 as a clinically relevant regulator of sarcoma progression and immune modulation. By engaging an AKT/c-Myc/PD-L1 signaling axis and shaping an immune-excluded tumor microenvironment, EXT2 may serve as a prognostic biomarker and a potential therapeutic target in selected sarcoma subtypes, warranting further subtype-specific and mechanistic investigation.

In clinical settings, regenerating critical-sized calvarial bone defects presents substantial problems owing to the intricacy of surgical methods, restricted bone growth medications, and a scarcity of commercial bone grafts. To treat this life-threatening issue, improved biofunctional grafts capable of properly healing critical-sized bone defects are required. In this study, we effectively created anti-fracture hydrogel systems using spongy-like metal-organic (magnesium-phosphate) coordinated chitosan-modified injectable hydrogels (CPMg) loaded with a bioinspired neobavaisoflavone (NBF) component. The CPMg-NBF hydrogels showed outstanding anti-fracture capabilities during compression testing and retained exceptional mechanical stability even after 28 d of immersion in phosphate-buffered saline. They also demonstrated prolonged and stable release profiles of Mg2+ and NBF. Importantly, CPMg-NBF hydrogels revealed robust biphasic mineralization and were non-toxic to MC3T3-E1 cells. To better understand the underlying mechanism of Mg2+ and NBF component, as well as their synergistic effect on osteogenesis, we investigated the expression of key osteogenic proteins in the p38 MAPK and NOTCH pathways. Our results showed that CPMg-NBF hydrogels greatly increased the expression of osteogenic proteins (Runx2, OCN, OPN, BMPS and ALP). In vivo experiments showed that the implantation of CPMg-NBF hydrogels resulted in a significant increase in new bone growth within critical-sized calvarial defects. Based on these findings, we expect that the CPMg-NBF supramolecular hydrogel has tremendous promise for use as a therapeutic biomaterial for treating critical-sized calvarial defects.

Bones can fulfill functions in movement, attachment, and protection of internal organs. Bone diseases caused by ageing, trauma, infection, and other reasons may seriously affect the daily life of patients. Magnesium ions are closely associated with the maintenance of bone health. Integrating magnesium ions into delivery systems and hydrogels can improve their application, thus directly acting on the osteoblast cell lineage and influencing the proliferation and differentiation of relevant cells. The slow release of magnesium ions allows for their effects on the target site for a long time, reducing the clearance of magnesium ions in the body, which significantly contributes to bone repair. Magnesium-based bioalloy scaffolds have received widespread attention for their favourable biocompatibility, degradability, and bone-forming properties and play an important role in bone regeneration and repair. This article presents a review on the role and mechanism of magnesium-containing materials in bone repair and regeneration. By discussing the current challenges and future directions for magnesium-containing biomaterials, new insights are provided into the development of these materials in the field of orthopaedics. In conclusion, magnesium-containing biomaterials have great application value in orthopaedics.

Osteoarthritis (OA) is recognized as the most common joint disease with serious public health implications. Cardiovascular health (CVH) is also an issue that is frequently emphasized in public health and has an impact on a variety of diseases and mortality rates. This study aims to investigate the association of CVH with the morbidity of OA. And explore the association of CVH with both all-cause and cardiovascular disease (CVD) mortality among US adults with OA. This study utilized data from the National Health and Nutrition Examination Survey 2005–2018, which included 21,289 adults aged ≥ 20, representing 137,912,968 Americans. CVH was assessed by Life’s Essential 8 (LE8) includes 4 behavior and 4 factor metrics. Total LE8 scores were calculated from the unweighted average on a 0–100 scale and were categorized as high (80–100), moderate (50–79), and low (0–49) CVH. Multivariable logistic regression explored the association of OA with CVH. Cox proportional hazards regression examined LE8 associations with mortality. Adjusting for confounding variables, per 10 points LE8 increase, the OR was 0.82 in association with OA, while OA morbidity were decreased by 30

Abstract As an etiological factor underlying physical and mental disability in humans, peripheral nerve injuries (PNIs) can induce pain, sensory impairment, and disability. Despite their regenerative ability, peripheral nerves cannot self‐repair after severe defects. While nerve grafting is the gold standard for the treatment of PNIs, it is limited by graft versus host reactions, surgical complications, and limited donor nerves. As the field of material science continues to develop, hydrogels have been proposed for use in PNI repair after their biomodification, targeted modification, or loading with biological factors and cells. This article reviewed research advances in hydrogels used for PNI repair, including simple hydrogels and composite functionalized hydrogels loaded with biological factors and cells. Based on the findings from these reviews, we determined that further clarification of the mechanisms of action for hydrogels and loaded biological factors in modulating cellular functions is necessary. In addition, there is a need to further explore the synergistic effect of novel functionalized hydrogels with other biological, physical, or biochemical factors. While clinical trials are still limited, scientific efforts are expected to promote the application of hydrogels in the field of PNI repair.

Osteoarthritis (OA) is a long-standing degenerative condition of the joints, defined by the progressive loss of articular cartilage accompanied by ongoing inflammation. For OA to be effectively treated, reducing cartilage breakdown and enhancing its regeneration are essential objectives. However, OA involves chronic sustained inflammation, making it difficult to protect cartilage and promote its regeneration under inflammatory conditions for effective OA treatment. To address these challenges, a kartogenin (KGN)-loaded biomimetic targeting system, designated CM@Lipos-KGN, was developed by integrating the anti-inflammatory properties of M2 macrophage membranes and the ability of KGN to promote chondrogenic differentiation of BMSCs. CM@Lipos-KGN was obtained by encapsulating KGN within liposomes coated with M2 macrophage cell membranes. It was found that CM@Lipos-KGN effectively protects cartilage in vitro by simultaneously suppressing inflammation and chondrocyte ferroptosis while maintaining chondrocyte metabolic homeostasis. Additionally, CM@Lipos-KGN significantly enhances the directional chondrogenic differentiation of BMSCs under inflammatory conditions in vitro, thereby facilitating cartilage regeneration. Animal experiments confirmed that CM@Lipos-KGN slowed the progression of OA and safeguarded cartilage by enhancing the expression of cartilage-associated proteins such as aggrecan and collagen II while simultaneously suppressing the levels of catabolic enzymes ADAMTS5 and MMP13. These findings underscore the considerable promise of CM@Lipos-KGN as a nanotechnology-based therapeutic platform for OA treatment.

The inflammatory microenvironment mediated by synovial macrophages, particularly the pro-inflammatory M1 subtype, plays a central role in OA progression and represents a critical therapeutic target. However, delivery strategies that enable efficient and selective targeting of M1 macrophages for modulating the inflammatory microenvironment are still limited. To address this challenge, we developed a glucose-functionalized nanoparticle system (Ber-MNPs) to deliver berberine directly to pro-inflammatory M1 subtype macrophages—via GLUT1-mediated targeting, thereby modulating the inflammatory microenvironment to alleviate OA progression. The Ber-MNPs exhibited excellent targeting specificity toward M1 macrophages in vitro. In addition, Ber-MNPs can suppress macrophage polarization toward the pro-inflammatory M1 phenotype, promote their transition to the anti-inflammatory M2 phenotype, and downregulate inflammatory cytokines, thereby protecting chondrocytes from catabolic damage. In a surgically induced OA mouse model, intra-articularly administered Ber-MNPs exhibited prolonged joint retention and mitigated OA progression by attenuating synovial inflammation and preserving cartilage integrity. Together, this study establishes a M1 macrophage-targeted nanotherapeutic platform that achieves precise inflammatory modulation, offering a new strategy for reshaping the synovial inflammatory microenvironment and achieving effective delay of OA progression.

Background: Skeletal muscle atrophy is a common musculoskeletal disorder that significantly reduces patient quality of life. Long non-coding RNA (lncRNA) XLOC_015548 has been identified as a pivotal regulator of C2C12 myoblast proliferation and differentiation. However, its role in mitigating denervation-induced muscle atrophy and the underlying mechanisms remain unclear. Methods: We employed lentiviral-mediated stable expression of XLOC_015548 in C2C12 myoblasts and skeletal muscle-specific XLOC_015548-edited mouse models to investigate the function of this lncRNA. Muscle atrophy models were established in vitro by glucocorticoid-induced atrophy with dexamethasone (DEX) and in vivo by sciatic nerve transection-induced denervation. The MEK inhibitor U0126 was used to assess the role of the growth arrest and DNA damage-inducible 45 gamma/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Gadd45g/MEK/ERK) signaling pathway. Results: Overexpression of XLOC_015548 significantly activated the MEK/ERK signaling pathway (p < 0.05) by downregulating Gadd45g expression (p < 0.05) and promoting its cytoplasmic localization, thereby enhancing cell proliferation and myotube formation. Furthermore, XLOC_015548 reduced the level of reactive oxygen species (ROS) (p < 0.01), stabilized the mitochondrial membrane potential, and alleviated DEX-induced oxidative stress. These protective effects were partially reversed by U0126, confirming the involvement of the MEK/ERK pathway. Skeletal muscle-specific overexpression of XLOC_015548 in vivo significantly reduced denervation-induced muscle atrophy (q < 0.05) and increased the muscle fiber cross-sectional area. Conclusion: XLOC_015548 plays a critical role in promoting myogenic differentiation and protecting against muscle atrophy by regulating Gadd45g expression, activating the MEK/ERK signaling pathway, and reducing oxidative stress. These findings underscore the therapeutic potential of XLOC_015548 in skeletal muscle atrophy, and provide a foundation for lncRNA-based treatment strategies.

Peripheral nerve disease is commonly encountered in orthopedics, neurology, and neurosurgery. Due to its large population, a substantial number of patients are affected by these conditions in China. Peripheral nerve disease has a high disability rate and current treatments show poor clinical efficacy, resulting in a heavy burden for patients and the country's healthcare system. Defensins are widespread proteins, commonly found in animals, plants, and fungi, with multiple subtypes able to kill a variety of pathogens. As regulatory factors of the immune system, defensins influence bodily function by participating in inflammatory processes, immune responses, and pathogen resistance; they can affect all stages of nerve conduction and play an important role in lesions of peripheral and effector nerves. This article provides a review of the possible roles and mechanisms of defensins in peripheral nerve disease.

Persistent reactive oxygen species (ROS) stress, excessive inflammation, insufficient angiogenesis, and inadequate neurogenesis severely hinder peripheral nerve repair and remain inadequately addressed by current biomaterials. To overcome these challenges, we developed a multifunctional conduit system with a facile and efficient assembly process. Specifically, 4-amino-3-fluorophenylboronic acid (AFBA) functionalized hyaluronic acid (HP) was crosslinked with tannic acid (TA) through boronate ester bonds to obtain a dynamic hydrogel (HT), during which VEGF was encapsulated. Subsequently, HT was physically blended with NGF-encapsulated Gelatin Methacryloyl (GelMA) microspheres (MS). In the early stage of nerve injury, the ROS-rich inflammatory microenvironment triggered the oxidative cleavage of boronate ester bonds, resulting in rapid degradation of the HT hydrogel and the corresponding release of TA and VEGF. Subsequently, the released TA, enriched with phenolic hydroxyl groups, effectively continued to scavenge excessive ROS and promoted macrophage polarization toward the M2 phenotype, while VEGF facilitated early neovascularization at the injury site. Additionally, the UV-crosslinked MS ensured the sustained release of encapsulated NGF, thereby providing long-term neurotrophic support that enhanced Schwann cell activity and promoted axonal elongation. The in vivo application of the HT/MS hydrogel with chitin conduits demonstrated effective nerve regeneration across a 10-mm defect in rats.

Osteoporotic bone defects remain a major clinical challenge due to impaired osteogenesis, insufficient angiogenesis, excessive osteoclast activity, and increased susceptibility to infection. To address these issues, we developed an injectable phosphocreatine-grafted gelatin hydrogel (GGP) incorporating hierarchically structured Zn-Cu particles functionalized with a teriparatide (PTH)/strontium–zinc phosphate (SrZnP) hybrid coating. This multifunctional hydrogel was fabricated via enzymatic and ionic coordination crosslinking, yielding improved mechanical properties and sustained release of Zn2+, Sr2+, and PTH. In vitro evaluations demonstrated that the hydrogel enhanced BMSC proliferation, osteogenic differentiation, and mineralization, promoted HUVEC migration, tube formation, and angiogenic marker expression, and simultaneously inhibited osteoclastogenesis and bacterial growth. Transcriptomic analysis and inhibitor experiments revealed a dual paracrine mechanism mediating bone–vascular coupling: BMSC-derived HIF-1α–VEGF signaling facilitated angiogenesis, while HUVEC-derived PI3K–Akt–BMP-2 signaling enhanced osteogenesis. In vivo, the PTH/SrZnP@ZnCu-GGP hydrogel significantly accelerated bone regeneration and neovascularization in an ovariectomized rat calvarial defect model, accompanied by upregulated expression of BMP-2, RUNX2, p-Akt, and CD31. Collectively, this injectable hydrogel system offers a robust and translationally feasible strategy for coordinated osteogenesis–angiogenesis coupling, osteoclast suppression, and antibacterial defense, thus holding strong potential for the regeneration of osteoporotic bone defects.

Introduction: Hydrogels, owing to their excellent biocompatibility, tunable physicochemical properties, and ability to mimic the extracellular matrix, have emerged as promising materials for the treatment of musculoskeletal disorders, including osteoarthritis, intervertebral disc degeneration, and bone injuries. Recent advancements in smart hydrogels and multifunctional composites have further broadened their applications in drug delivery, tissue engineering, and regenerative medicine. However, despite growing interest in this field, current reviews often lack systematic, data-driven insights into the evolving research landscape. Methods: To address this gap, we conducted a bibliometric analysis using CiteSpace and VOSviewer to quantitatively map the development of hydrogel-related research in musculoskeletal disorders over the past two decades. Key parameters analyzed included publication trends, influential countries and institutions, collaborative networks, keyword evolution, and research hotspots. Results: Our analysis revealed a steady growth in publications, with China and the United States emerging as leading contributors. Prominent institutions and authors were identified, along with landmark publications that have shaped the field. Keyword co-occurrence analysis highlighted emerging themes such as injectable hydrogels, 3D bioprinting, and osteochondral regeneration. The most frequently studied disease targets included osteoarthritis, intervertebral disc degeneration, and bone defect repair. Conclusions: This comprehensive bibliometric overview offers valuable insights into the current status and future directions of hydrogel research in musculoskeletal disorders. It highlights key trends, influential contributors, and emerging hotspots, providing a solid foundation for advancing interdisciplinary collaborations and accelerating the clinical translation of hydrogel-based therapies.

BackgroundDisulfidptosis is a newly discovered form of cell death associated with tumorigenesis, particularly under oxidative stress and metabolic disorder conditions. Currently, the biological mechanisms of disulfidptosis-related genes (DRGs) in head and neck squamous cell carcinoma (HNSCC) remain unclear.MethodsThe study includes sections on methodologies, data sources, clinical data collection, subtype establishment, identification and analysis of differentially expressed genes, genetic variation, and the construction and validation of a DRG prognostic model. Various analyses are conducted, including the relationship between the risk scores model and clinicopathological features, immune status, immune checkpoints, tumor mutational burden (TMB), microsatellite instability (MSI), ESTIMATE, mRNAsi, and drug sensitivity. The study also covers single-cell analysis and DNA methylation analysis of DRGs, and the prediction of potential microRNA and long non-coding RNA target genes. Prognostic DRGs expression in HNSCC is validated through RT-qPCR and immunohistochemistry. The model’s predictive capability is confirmed using external validation cohorts from GEO datasets and clinical tissue samples. The role of DSTN in HNSCC is further validated through gene knockout experiments.ResultsWe identified four valuable genes (SLC3A2, NUBPL, ACTB, DSTN) and constructed a prognostic model, along with identifying two DRG-related subtypes. Analysis of the DRG risk score revealed that the low-risk group had a better prognosis compared to the high-risk group. Significant correlations were found between the DRG risk score and clinical features, immunotherapy response, drug sensitivity, and genes related to RNA epigenetic modifications. Low-risk HNSCC patients were identified as potential beneficiaries of immune checkpoint inhibitor (ICI) therapy. A regulatory axis involving DSTN, hsa-miR-181c-5p, LUCAT1, and IGFL2-AS1 was constructed for HNSCC. RT-qPCR and IHC data further validated the upregulation of prognostic DRGs in HNSCC. The prognostic model demonstrated excellent predictive performance for the prognosis of HNSCC patients. Additionally, DSTN was significantly overexpressed in tumor cells; its knockdown inhibited tumor cell proliferation, migration, and invasion.ConclusionThe prognostic model effectively predicts HNSCC outcomes, with better prognosis in the low-risk group. DSTN upregulation promotes tumor growth, and its knockout inhibits proliferation, migration, and invasion.

Polyphenols, a diverse group of plant-derived compounds known for their antioxidant and anti-inflammatory properties, have garnered increasing attention for their therapeutic potential in osteoarthritis (OA). However, a comprehensive bibliometric analysis of the research landscape in this field has been lacking. This study aimed to systematically evaluate global research trends, knowledge structure, and emerging hotspots related to polyphenols in OA. Publications from 2000 to 2025 were retrieved from the Web of Science Core Collection and analyzed using bibliometric tools such as VOSviewer and CiteSpace. A total of 1,436 publications were identified, demonstrating a steady rise in annual output, with China and the United States emerging as the most prolific contributors. Keyword co-occurrence and citation burst analyses revealed that curcumin, resveratrol, EGCG, inflammation, oxidative stress, and cartilage degeneration are central research themes. Notably, recent trends highlight increasing interest in ferroptosis, gut microbiota, and targeted drug delivery systems in the context of polyphenol-based OA therapies. This bibliometric analysis provides a comprehensive overview of the current status and developmental trajectory of polyphenol research in OA, offering valuable insights to guide future studies and foster interdisciplinary collaboration.

Background: Peripheral nerve injury is a challenging orthopedic issue in clinical management that often leads to limb dysfunction or even disability in severe cases. A thorough exploration of the repair process of peripheral nerve injury and the underlying mechanism contributes to formulate more effective therapeutic strategies. Methods: In the present study, we established a sciatic nerve transection injury model in Sprague-Dawley (SD) rats. A 12-week compensatory repair of sciatic nerve transection injury using a chitin cannula for small gap anastomosis was then performed via sleeve jointing the proximal common peroneal nerve to the distal tibial nerve and common peroneal nerve, with a 2 mm interval. Compensatory repair via small gap amplification was observed via gross observation of nerve specimen, osmic acid staining, and electrophysiological stimulation of sciatic nerve branches of the tibial and common peroneal nerve. Rat limbs were observed, and the functional recovery of effector muscles of the gastrocnemius and tibialis anterior muscles was assessed through weighing the muscle wet weight, Hematoxylin and Eosin (H&E) staining, and muscle strength detection. H&E staining, Masson staining, and toluidine blue staining were performed to observe the morphological changes of the dorsal root ganglion. Positive expressions of key proteins involved in the Phosphatase and tensin homologue deleted on chromosome ten (PTEN)-protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, including PTEN, AKT, mTOR, Toll-like receptor 4 (TLR4), and Caspase9 in the dorsal root ganglion during compensatory repair of sciatic nerve after injury via small gap amplification, were detected by immunohistochemical staining. Results: It is found that the compensatory repair of sciatic nerve transection injury using a chitin cannula for small gap anastomosis via sleeve jointing effectively restored the continuity, number of myelinated nerve fibers, and nerve conduction velocity. It promoted toe abduction recovery, improved muscle fiber morphology and increased the wet weight and muscle strength of the gastrocnemius muscle and tibialis anterior muscle. Moreover, it increased the number of neurons and nerve fibers, and improved their morphology. Downregulated PTEN, TLR4, and Caspase9 in the dorsal root ganglia and upregulated AKT and mTOR were observed after small gap amplification than those of the transection injury group, which were closer to those of the control group. Conclusions: Compensatory repair of sciatic nerve transection injury using a chitin cannula for small gap anastomosis via sleeve jointing can restore the morphology and function of the sciatic nerve, effector muscles, and corresponding dorsal root ganglia by activating the PTEN-AKT/mTOR signaling pathway in the dorsal root ganglia. Our findings provide novel therapeutic targets for peripheral nerve injuries.

Abstract Background The incidence of osteoarthritis (OA) increases with each passing year. The degeneration of the meniscus and synovium is considered the initial factor of knee osteoarthritis (KOA), but their synergistic mechanism has not been clarified. Methods In this study, single-cell RNA sequencing (scRNA-seq) was employed to establish 16 normal or degenerated meniscus samples and 6 synovium samples based on the meniscus and synovium tissues of 16 patients. A cell atlas comprising 124,026 single cells in total was established (including 8 patients from the public database The Genome Sequence Archive for Human [GSA-Human] PRJCA008120). Based on that, the meniscus/synovium microenvironment homeostasis and the crosstalk between both during their degeneration were explored. Results In this study, the cell types in the meniscus and synovium were analyzed. Besides, new fibroblast subtypes related to the degeneration of the meniscus and synovium were identified. Additionally, the interaction between meniscus and synovium and different cell subtypes was analyzed. Moreover, the mechanism involving vascular growth, immune cell infiltration, and common or different genes during the degeneration of synovium and meniscus tissues was investigated. Conclusions This study may provide the atlas of synovium and meniscus with the largest number of cells in osteoarthritis (OA) to date, reflecting the comprehensive cellchat of synovium and meniscus during degeneration. These findings suggested that the synovium was involved in the crosstalk of intra-articular tissues (synovium/meniscus), thus participating in the degeneration in OA.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by the degradation of articular cartilage while sustained inflammation and ferroptosis have been demonstrated to play crucial roles in the progression of OA. It is an effective strategy to fabricate nanomedicines for OA treatment. However, current research primarily concentrates on anti-inflammation, whereas nanomedicine systems for anti-ferroptosis in OA treatment are rarely reported. Additionally, there are few studies integrating inflammation inhibition with anti-ferroptosis within a single system to ameliorate OA progression. In this study, we introduce a curcumin-loaded biomimetic nanosponge (CM@Cur-NPs) to alleviate OA by synergistically suppressing inflammation and ferroptosis. CM@Cur-NPs were obtained by encapsulating curcumin within polymeric nanoparticles and coating them with macrophage cell membranes. The in vitro and in vivo synergistic anti-inflammatory and anti-ferroptotic effects of CM@Cur-NPs were investigated. It was discovered that the CM@Cur-NPs significantly reduced proinflammatory cytokines (TNF-α, IL-6), iNOS, ROS, and apoptosis levels of chondrocytes while concurrently increasing the anti-inflammatory cytokine (IL-4) and extracellular matrix (ECM) content in vitro. We also found that CM@Cur-NPs decreased the expression of the ferroptosis marker Fe2+, ACSL4, and MDA, coupled with an increase in the levels of SLC7A11 and GPX4 of chondrocytes. Lipid peroxidation of chondrocytes was attenuated by CM@Cur-NPs as well. In vivo results indicated that CM@Cur-NPs effectively alleviated OA progression and achieved cartilage protection by upregulating Aggrecan and collagen II expression, along with downregulating ADAMTS5 and MMP13 expression. This study demonstrated that CM@Cur-NPs exhibited enhanced chondroprotective effects through synergistic anti-inflammatory and anti-ferroptotic actions. It is a promising approach to integrate inflammation and ferroptosis inhibition by bioactive nanomaterials for OA treatment.