[This retracts the article DOI: 10.3892/ol.2016.5046.].

Abstract Cells in vivo experience mechanically diverse microenvironments in which physical confinement is a pervasive but poorly understood regulator of their behavior and fate. Whether and how mechanical confinement governs immune cell differentiation remains unknown. Here, we reveal that a mechanical cue — long-term confinement is sufficient to drive monocyte-to-macrophage differentiation through a mechanoepigenetic pathway. In vivo, differentiating monocytes exhibited flattened nuclei in the liver capsule, indicative of confinement by surrounding stromal and parenchymal structures. Using a custom cell confiner to recapitulate this confined niche, we found that confinement induces macrophage-like protrusive architectures, enhances motility, and upregulates macrophage-associated genes in RAW264.7 and THP-1 monocyte-lineage cells. Notably, extending this paradigm to primary murine bone-marrow, human umbilical-cord, and tissue-derived hepatic-associated monocytes yielded similar outcomes, thus enhancing phagocytic capacity, directly demonstrating that mechanical confinement can program monocytes into macrophages. Mechanistically, we found that confinement activates KDM6B, leading to H3K27me3 demethylation, which derepresses macrophage-specific transcriptional programs. Pharmacological inhibition of KDM6B with GSK-J4 restored H3K27me3 and blocked macrophage differentiation both in vitro and in vivo. These findings define a KDM6B–H3K27me3 axis that links nuclear mechanics to transcriptional reprogramming, positioning mechanical confinement as a “super-enhancer–like” cue for engineer macrophage function in therapeutic and bioengineering contexts.

Osteoclasts and osteoblasts play critical roles in bone remodeling, and their dysregulation leads to pathological bone loss. However, the precise mechanisms underlying the regulation of differentiation remain unclear. This study investigated the role of the transcriptional regulator Zinc Finger Matrin-Type 1 (Zmat1) in both osteoclastogenesis and osteoblastogenesis. Zmat1 deficiency resulted in decreased osteoclast activity, and bone resorption. Mechanistically, ZMAT1 was significantly upregulated during osteoclast differentiation and acted as a transcriptional repressor of the E3 ubiquitin ligase TRIM46, which regulates YAP1 degradation via K48-linked ubiquitination. Furthermore, Zmat1 deficiency enhanced osteoblast activity and bone formation. These findings highlight a novel ZMAT1/TRIM46/YAP1 axis, providing new insights into the transcriptional regulation of both osteoclast and osteoblast differentiation, and present potential therapeutic targets for osteoporosis.

Emerging evidence highlights the pivotal role of KISS1 in cancer metastasis; however, there remains a dearth of pancancer analyses, particularly concerning immunotherapy. Here, we conducted a comprehensive investigation of KISS1 across various cancers, with a specific focus on breast cancer, using TCGA and GTEx datasets. We observed a tissue context-dependent role function of KISS1 in tumor metastasis, which exhibited suppressive effects in various tumors but promoted the metastatic phenotype in breast cancer. Our study revealed a noteworthy disparity between KISS1 expression at the mRNA and protein levels, indicating potential posttranslational modifications within cancer cells. Moreover, KISS1 is significantly associated with immune cell infiltration and immunosuppressive cells, suggesting its crucial role in modulating tumor immunotherapy. Intriguingly, our investigation also elucidated KISS1’s involvement in promoting breast cancer metastasis, thereby providing valuable insights into the molecular underpinnings of this process. Furthermore, we validated the presence of posttranslational modifications of KISS1 in breast cancer, adding to our understanding of its role in tumorigenesis. By shedding light on the tissue context-dependent function of KISS1 and its implications for immunotherapy, our pancancer study offers novel perspectives on the oncogenic roles of KISS1 and provides potential avenues for the development of targeted therapies and diagnostic biomarkers.

Articular cartilage defects are inherently difficult to treat given the tissue’s avascularity and minimal intrinsic regenerative capacity. Although stem cell-derived organoids offer promise for cartilage regeneration, insufficient dimensional scalability and poor host-tissue integration remain key limitations. Here, we developed a 3D-bioprinted piezoelectric cartilage-bone integrated organoid system using two functionally distinct bioinks: a chondrogenic matrix of methacrylated chondroitin sulfate (ChSMA), barium titanate (BTO) nanoparticles, and TGF-β and an osteogenic matrix of gelatin methacrylate (GelMA), BTO, and nano-hydroxyapatite (nHA). This bilayer design establishes compartment-specific microenvironments that guide bone marrow mesenchymal stem cell (BMSC) differentiation toward chondral and osseous lineages while maintaining spatial segregation between the two compartments. Incorporated BTO nanoparticles convert mechanical stimulation into localized bioelectrical cues, enhancing cellular responsiveness and tissue maturation. The biomimetic osseous layer provides structural anchorage at the defect site. Our results demonstrate stratified extracellular matrix formation with compartment-specific compositions, offering a mechanistically grounded approach for osteochondral defect repair.

Background:Ankylosing spondylitis (AS) is a chronic immune-mediated inflammatory disease in which genetic susceptibility, mucosal immunity, and environmental factors converge. Growing evidence indicates that gut microbiota dysbiosis is closely involved in AS pathogenesis, yet the evolution of this research field and the underlying functional mechanisms remain to be systematically clarified. Methods:The study performed an analysis of studies on AS and gut microbiota retrieved from the WOSCC, Scopus, and PubMed. Publication trends, collaboration networks, co-citation patterns, and keyword clusters were analyzed to identify major research themes and emerging hotspots in this field. Results:The analysis revealed a progressive shift from descriptive microbiota profiling to mechanistic and causal investigations. Core research themes included microbial dysbiosis, intestinal barrier dysfunction, mucosal immune activation, microbial metabolites, and key inflammatory pathways. Studies increasingly emphasize functional and pathway-level analysis rather than focusing on individual microbial taxa. Mendelian randomization further strengthened causal inference and highlighted the potential of microbiota-related signatures for disease stratification and therapeutic response. Conclusion:These findings support a disturbed gut-joint axis as a central feature of AS and underscore the role of functional microbial pathways in immune dysregulation. Integrating standardized multi-omics data with causal validation and refined clinical phenotyping may facilitate the identification of actionable microbial targets and advance microbiota-informed precision strategies for AS.

OBJECTIVE:To explore the role of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) in promoting the motility and functional enhancement of tendon-derived stem cells (TDSCs) and assess their potential in tendon regeneration and repair. METHODS:In vitro experiments involved the isolation and characterization of BMSCs-Exos from cultured bone marrow mesenchymal stem cells. The exosomes were analyzed for their size, morphology, and protein content using nanoparticle tracking analysis (NTA) and western blotting for exosomal markers. Tendon stem cell (TDSC) migration was assessed using a scratch assay. For in vivo analysis, a rat tendon injury model was used to evaluate the therapeutic effects of BMSCs-Exos on tendon healing and tissue regeneration. Rats were injected with BMSCs-Exos at varying doses, and the healing process was monitored through histological analysis and assessment of angiogenesis and collagen deposition. RESULTS:The results demonstrated successful extraction of BMSCs-Exosomes, confirmed by positive expression of exosomal markers (CD9, CD63, and ALIX) and the absence of cellular contaminants via western blot and uniform particle size (median 134.8 nm, concentration 8.7 × 1011 particles/mL). Immunofluorescence showed a time-dependent uptake of purified PKH26-labeled Exosomes by TDSCs. While no significant difference in proliferation or survival was observed, Exosomes promoted scratch closure (p < 0.05) and osteogenic differentiation, as evidenced by increased ALP activity, calcium deposition (ARS), and upregulation of Runx-2/COL-1 expression. In vivo, Exosomes promoted collagen synthesis (COL-1) and angiogenesis (CD31), improving tendon structural integrity (H&E staining). CONCLUSION:BMSCs-Exos demonstrate therapeutic potential for tendon repair by orchestrating key regenerative processes, including tendon stem cell motility and differentiation.

Meniscus injuries present dual challenges, including limited regenerative capacity due to avascularity and a persistent inflammatory microenvironment following injury. Herein, we reported a decellularized meniscus extracellular matrix (dmECM) scaffold functionalized with a hyaluronic acid (HA) and celecoxib (CLX) grafted (dmECM-HC) through carbodiimide chemistry. This design integrates acute immunomodulation with long-term regenerative support. The dmECM scaffold recapitulated the ECM architecture of the native meniscus, while the HA-CLX enhanced its elasticity and immunomodulatory capacity. The dmECM-HC scaffold exhibited superior mechanical performance retention during 1000 cyclic compression cycles and demonstrated sustained release of CLX for up to 7 weeks in vitro. It promoted M2 polarization of lipopolysaccharide (LPS)-stimulated macrophages and effectively modulated acute inflammation through Toll-like receptor, tumor necrosis factor (TNF), and Nuclear factor kappa-B (NF-κB) signaling pathways. Together with its robust antioxidant capacity, the dmECM-HC scaffold provided a pro-regenerative microenvironment. Furthermore, it significantly facilitated stem cell recruitment and ECM deposition. In a rabbit meniscus defect model, the dmECM-HC scaffold promoted tissue repair by activating NF-κB and calcium signaling pathways. At 12 weeks, it significantly enhanced tissue maturation and collagen arrangement in the defect area and mitigated cartilage degeneration. This strategy guides meniscus healing with a dual function by modulating the inflammatory environment while providing biomimetic structural support.

To jointly capture antigen-binding affinity and paired heavy-light-chain sequences at scale has remained a bottleneck for monoclonal antibody discovery. Here, we present Antigen Affinity BCR-seq (AAB-seq), a high-throughput single-cell sequencing platform that can obtain the relative antibody-antigen affinity of thousands of paired native BCR sequences. AAB-seq employs dual-labeled antigens and DNA-barcoded anti-light-chain antibodies to compute an AAB score that is proportional to antibody-antigen binding strength. Integrated with a rapid, low-cost direct cloning workflow, it enables affinity-guided antibody retrieval without de novo antibody gene synthesis. Validated against ovalbumin and SARS-COV-2 RBD, AAB-seq discovered potent antibodies whose AAB score correlates strongly with ELISA, including novel SARS-COV-2 neutralizing antibodies with potent effector functions. Together, AAB-seq accelerates antibody screening and potentially provides large-scale sequence-affinity datasets for machine learning-driven therapeutic antibody design and development.

Bone metastasis is a major cause of morbidity and poor survival in solid tumors, yet its progression is often recognized only after overt lesion formation. In this review, we propose a circulating tumor cell/disseminated tumor cell (CTC/DTC)-centered temporal framework that conceptualizes bone metastasis as a sequential and selection-driven process linking dissemination, bone-specific homing, DTC establishment, dormancy, and reactivation. We summarize the key cellular and molecular mechanisms governing these transitions, with particular emphasis on tumor cell plasticity, bone marrow niche interactions, and the dormancy-reactivation interface. We further discuss the translational relevance of this approach for risk stratification, minimal residual disease assessment, treatment monitoring, and emerging experimental strategies, including single-cell multi-omics, spatial omics and biomimetic bone microenvironment models. This perspective shifts the view of bone metastasis from a static, imaging-detectable lesion to a time-resolved biological process and highlights potential windows for earlier risk assessment, disease monitoring, and biology-guided intervention.

The assessment of motor function recovery in spinal cord injury (SCI) mouse models traditionally relies on semi-quantitative methods like the Basso Mouse Scale (BMS), which are prone to inter-observer variability and are labor-intensive. To address these limitations, this study aimed to develop and validate novel, objective kinematic metrics for a more precise and automated evaluation of motor function. Using the DeepLabCut software package to analyze locomotion videos of SCI mice, we applied Permutation Feature Importance (PFI) to identify key joints associated with motor recovery. Based on this data-driven approach, we engineered four new indicators: max horizon-hip-hindpaw angular velocity to quantify hindlimb movement speed and range, average horizon-hindpaw-hindpaw tip angle to assess foot posture (dorsal versus plantar contact), neck swing times to evaluate trunk stability at later recovery stages, and step difference to measure forelimb-hindlimb coordination. Our results demonstrate that these novel metrics exhibit strong correlations with manual BMS scores and capture distinct aspects of motor recovery. Furthermore, integrating these indicators into a Random Forest regression model improved the sensitivity of automatic assessment of BMS compared with models using only previously established metrics. In conclusion, these novel kinematic indicators provide a more objective, sensitive, and efficient framework for assessing motor function in SCI mice, thereby enhancing experimental reproducibility and offering a powerful tool for preclinical research.

PURPOSE:Limited efficacy of current treatments for chordoma calls for novel therapeutic options. Combination of immune checkpoint inhibitors and antiangiogenic drugs has altered the landscape of cancer treatment but has rarely been investigated in chordoma. METHODS:An investigator-initiated, single-center, phase II trial was conducted on camrelizumab (a PD-1 inhibitor, 200 mg once every 2 weeks) plus apatinib (an antiangiogenic drug, 250 mg and 500 mg on alternate days, that is, 250 mg one day, 500 mg the next day, alternating) in patients with refractory chordoma for 4-week cycles. The primary end point was the objective response rate (ORR) per RECIST version 1.1. Secondary end points included ORR per Choi criteria, progression-free survival (PFS), overall survival, the disease control rate, median duration of response (mDoR), safety, and quality of life. The trial is registered with Chictr.org.cn (ChiCTR2100042938). RESULTS:Of the 38 patients initially screened between September 2021 and October 2024, 33 were enrolled. Median follow-up duration was 20.8 months (IQR, 13.35-26.55). ORR was 24.2% (8/33 [95% CI, 11.1 to 42.3]) per RECIST 1.1 and 48.5% (16/33 [95% CI, 30.8 to 66.5]) per Choi criteria. The median PFS was 28.4 months (95% CI, 13.53 to 43.28). The mDoR was not reached per RECIST 1.1 and was 22.2 months (95% CI, 12.5 to not reached) per Choi criteria. CDKN2A copy-number deletion or homozygous deletion was found to associate with worse prognosis. The most common grade 3 or 4 treatment-related adverse events included increased aspartate aminotransferase (13 [39.4%]) and increased alanine aminotransferase (11 [33.3%]). No treatment-related deaths occurred. CONCLUSION:Combination of camrelizumab and apatinib offered encouraging efficacy with manageable toxicity in chordoma treatment. CDKN2A alterations are associated with worse prognosis and may prove to be a potential biomarker for treatment selection.

Following spinal cord injury (SCI), neuroinflammation driven by lipid-laden macrophage foam cells is a key pathology, yet how these cells manage their lipid homeostasis is unclear. We delineate a neuroprotective axis in which macrophages deploy apolipoprotein E (APOE) to transfer intracellular lipids to neighboring cells, especially fibroblasts. Genetic ablation of Apoe disrupts this intercellular lipid transport, culminating in pathological lipid retention that activates the Hippo signalling cascade and transcriptionally induces complement component C1q. This excess C1q aberrantly tags intact synapses for excessive microglial pruning, leading to significant synaptic loss and impaired locomotor function recovery. Direct blockade of C1q using neutralizing antibodies recapitulated these neuroprotective effects, confirming C1q as the critical mediator. Crucially, macrophage-specific APOE re-expression reverses this entire cascade, preserving synapses and restoring locomotor function (BMS score: 4.81 ± 0.21 (Apoe) vs. 1.75 ± 1.28 (NC); Incline plane: 69.24° ± 2.33° (Apoe) vs. 51.66° ± 5.14° (NC) in Apoe−/− mice). These findings identify the APOE-Hippo-C1q pathway in macrophages as a novel therapeutic target for SCI.

To assess the association between myelodysplastic syndrome and de novo bone metastasis of urothelial carcinoma. A cohort of 145,719 patients with MDS and/or UTCA included from the surveillance, epidemiology, and end results (SEER) database was conducted to assess the risk of de novo bone metastasis of UTCA (DNBM-UTCA) in patients with previously diagnosed myelodysplastic syndrome (PD-MDS). The odds ratio for developing DNBM-UTCA between MDS and non-MDS patients was estimated. Weibull accelerated failure time model was applied to evaluate the survival outcomes of patients with UTCA. Our findings suggest that PD-MDS is a powerful risk factor for DNBM-UTCA (adjusted odds ratio, 6.428; 95

Poorly differentiated chordoma (PDC) is an exceptionally rare bone tumor with aggressive behavior and early recurrence. Evidence on the role and integration of chemotherapy remains limited. We aimed to share our institutional management experience and identify clinical prognostic factors in PDC. Five consecutive patients with axial PDC treated at our spinal tumor center (June 2021–June 2025) received surgery and anthracycline–ifosfamide (AI) chemotherapy. Neoadjuvant response was assessed by RECIST 1.1 and overall survival (OS) by Kaplan–Meier. We also reviewed histologically confirmed PDC cases reported in the literature with eligible treatment and outcome data, and compared OS by chemotherapy exposure and other factors using log-rank tests. The mean age in our series was 21.4 years; all tumors were mobile-spine PDC with INI-1 loss and brachyury positivity. Neoadjuvant AI-based combination therapy achieved a partial response (PR) in one patient. Median progression-free survival was 13 months and median OS was 21 months. In the pooled cohort (n = 30), there was a female predominance. Prior recurrence was associated with inferior OS. In descriptive comparisons, patients receiving chemotherapy-based multimodality therapy had longer observed OS than those receiving local therapy without chemotherapy, including among recurrent cases. Whereas radiotherapy did not show a comparable survival benefit, this finding should be interpreted cautiously given the likelihood of substantial selection bias and the palliative role of RT in many recurrent cases. AI-based chemotherapy, particularly in the neoadjuvant setting, was feasible and showed preliminary antitumor signal in selected patients. However, the patient who achieved a partial response also received apatinib; thus, the specific contribution of AI chemotherapy cannot be isolated. In the pooled exploratory analysis, patients who received chemotherapy had a longer observed median OS than those receiving local therapy alone. However, due to the broad definition of chemotherapy and high risk of selection bias, this finding is presented as purely descriptive and hypothesis-generating, and does not imply a meaningful association between chemotherapy and improved OS.

Background Osteoporosis (OP) is a common metabolic bone disease marked by decreased bone density and impaired bone structure. Conventional therapeutic strategies for OP are restricted by their non-specific targeting and long-term toxicity. Leveraging the gut-bone axis, we developed an engineered bacterial extracellular vesicles (BEVs) delivery system derived from probiotic Akkermansia muciniphila (AKK).Results These BEVs were engineered with a bone-targeting peptide SDSSD to generate BT-AKK-EVs. Through miRNA sequencing and functional experiments, we identified miR-21-5p as a pivotal effector molecule enriched within AKK-EVs. Mechanistically, BT-AKK-EVs delivered miR-21-5p to promote osteogenic differentiation while simultaneously inhibiting osteoclastogenesis via activation of the PI3K-AKT signaling pathway. Systemic administration of BT-AKK-EVs in ovariectomized mice resulted in their robust accumulation in bone tissues, significantly alleviating bone loss.Conclusions This study establishes engineered probiotic BEVs as a safe and efficient platform for targeted bone therapy and elucidates a concrete molecular mechanism of gut-bone communication through vesicle-packaged miRNA, offering a transformative strategy for treating metabolic bone disorders.

Infected wounds remain a significant clinical challenge due to bacterial resistance and impaired healing. Therefore, developing effective antibacterial agents and precise delivery systems is crucial for rapid wound repair. To address this, we constructed zeolitic imidazolate framework-8 (ZIF-8) nanoparticles loaded with the host defense peptide-mimicking glycine-poly(2-oxazoline) (Gly-POX) and incorporated them into methacrylated gelatin (GelMA) to prepare the Gel-P@Z nanocomposite hydrogel. The hydrogel integrates the following core design elements: the pH-responsive degradation of ZIF-8 enables targeted drug release within the infected microenvironment; Gly-POX, mimicking the structure of host defense peptides, exerts membrane-disruptive antibacterial activity against MRSA, which possesses a negatively charged cell membrane, through its positively charged side chains; and the GelMA hydrogel provides a three-dimensional extracellular matrix-like scaffold that supports cell adhesion and proliferation. Gel-P@Z exhibited a slow and sustained release of Gly-POX and achieved >99% antibacterial efficacy against drug-resistant bacteria without toxicity. Moreover, Gel-P@Z promoted macrophage polarization from M1 to M2 phenotype and enhanced efferocytosis, while also facilitating fibroblast migration and inducing contraction in ex vivo fascia explants. In a murine full-thickness MRSA-infected wound model, Gel-P@Z effectively cleared bacteria, modulated the inflammatory microenvironment, and promoted both angiogenesis and collagen deposition. RNA-seq analysis revealed that Gel-P@Z accelerated healing via upregulation of the TGF-β signaling pathway, driving fibroblast-to-myofibroblast transition and promoting tissue fibrosis. This work not only proposes a novel strategy for antibacterial polymer delivery but also offers a promising solution for the management of infected wounds.

Rheumatoid arthritis (RA) is a chronic autoimmune disease with limited therapeutic effectiveness of conventional biomaterials, which often lack targeted accuracy, delivery efficiency, and biocompatibility. Here, we present a biomimetically engineered carrier material using mitochondria as "living materials" to restore cell homeostasis in RA. The dual action carrier consists of a folic acid-modified macrophage membrane targeting activated M1 macrophages in RA joints, and it enables in situ mitochondrial transfer with more than twofold increase of delivery efficiency, which is a critical limitation of current approaches. By facilitating precise intracellular transfer of healthy mitochondria, and incorporating autophagy targeting chimera 4 (AUTAC4) in order to selectively destroy dysfunctional mitochondria, this design achieves complete mitochondrial renewal, increasing energy metabolism and homeostasis. In an RA model, the Dual-Action Mitochondrial Renewal Therapy (DAMRT) showed significant therapeutic potential. It could be used as a novel platform for treatment for RA and other mitochondrial dysfunction.

Bone metastasis can remodel the bone marrow microenvironment, yet how metastatic tumors reshape hematopoiesis and immunity across marrow regions remains poorly defined. Here, we profile a cross-cancer single-cell atlas with 126,986 cells by integrating bone marrow samples (tumor, involved, and distal sites) from liver, prostate, and kidney cancer bone metastases, as well as benign controls, resolving 7 major lineages and 66 subpopulations. We identified coordinated immune suppression and niche remodeling that innate cells rose in peri-tumoral marrow but dropped in tumor sites, while adaptive T/B cells progressively depleted and stromal/epithelial compartments expanded. We further revealed a shift in myelopoiesis toward immunosuppressive monocyte/macrophage states with GMP-level lineage bias, alongside impaired erythropoiesis and B lymphopoiesis driven by myeloid-like reprogramming of precursors. Tumor sites were enriched with exhausted/stressed T cells, linked to inhibitory progenitor-T cell interactions (e.g., LGALS9-HAVCR2 and CLEC2-KLRB1). Non-hematopoietic support signals (CXCL12-CXCR4, ICAM1-SPN) were attenuated, and tumor programs included a marrow-specific metaprogram with IGFBP3/NAMPT signaling predicted to further destabilize the HSC niche. Overall, our study offers an integrated framework for decoding the metastatic marrow ecosystem by jointly targeting hematopoietic distortion, stromal collapse, and immune dysfunction.