Connective Tissue Research最新文献

{"title":"Treadmill exercise induced differential miRNA expression in mouse femoral exosomes and upregulated osteogenesis-related miRNAs.","authors":"HaoYang Yu, Yang Wang, Biao Han, LiMing Liu, YaNan Li, HaiJian Du, Yong Guo","doi":"10.1080/03008207.2026.2720437","DOIUrl":"10.1080/03008207.2026.2720437","url":null,"abstract":"<p><strong>Purpose: </strong>Treadmill exercise promotes bone growth and remodeling in mice. Exosomes are key mediators of intercellular communication; bone or osteocyte-derived exosomes deliver miRNAs to osteoblasts to influence osteogenesis. Therefore, the study aims to profile miRNAs in femoral bone-derived exosomes of mice trained on a treadmill, and the exosomal osteogenesis-related miRNAs were identified through bioinformatics analysis and molecular biology experiments.</p><p><strong>Methods: </strong>Mice underwent treadmill training, after which exosomes were extracted from femoral bone and characterized, and miRNA expression profiles were analyzed using RNA sequencing. Thereafter, bioinformatics analysis of these differentially expressed miRNAs in the exosomes was performed, and two osteogenesis-related candidates, miR-3960 and miR-2137, were transfected into osteoblasts separately to validate their osteogenic effects.</p><p><strong>Results: </strong>Treadmill exercise markedly enhanced bone formation and improved bone microstructure. Bone-derived exosomes promoted osteogenesis, nine differentially expressed miRNAs were identified, with potential mechanistic links to bone morphometric parameters; their predicted target genes were enriched in pathways related to cellular growth, osteogenesis, axonal development, muscle tissue formation, and key signaling cascades such as PI3K/AKT and MAPK. Notably, the exosomal miR-3960 and miR-2137 were osteogenesis-related; qPCR analysis confirmed that both miRNAs were upregulated, consistent with the miRNA sequencing results. Further, transfection of miR-3960 or miR-2137 into osteoblasts enhanced osteogenesis.</p><p><strong>Conclusions: </strong>The miRNAs in exosomes from femur (almost osteocytes) of treadmill-trained mice participated not only in osteogenic differentiation (notably miR-3960 and miR-2137), but also showed potential in neural development and muscle growth. The findings offer novel insights into how running exercise benefits skeletal, muscular, and neural health.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"583-597"},"PeriodicalIF":1.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type I collagen alleviates <i>t</i>BHP-induced senescence in murine hippocampal neuronal HT22 cells through an F-actin/ferroptosis pathway.","authors":"Xiaoling Wang, Xin Li, Ling Ling, Toshihiko Hayashi, Kazunori Mizuno, Shunji Hattori, Hitomi Fujisaki, Weiwei Liu, Takashi Ikejima","doi":"10.1080/03008207.2026.2712480","DOIUrl":"10.1080/03008207.2026.2712480","url":null,"abstract":"<p><strong>Purpose: </strong>Neuronal senescence contributes to several age-related neurodegenerative diseases occurring with aging. Meanwhile, aging of our bodies is accompanied by the systemic dysregulation of type I collagen, the major component in the extracellular matrix. This study investigates whether type I collagen plays a protective role in neuronal senescence.</p><p><strong>Methods: </strong>Cellular senescence was assessed by evaluating senescence-associated β-galactosidase staining, cell area, senescence-associated proteins, and senescence-associated secretory phenotypes (SASPs); ferroptosis was evaluated using C11-BODIPY 581/591 fluorescent probe, GSH, MDA, and total iron assay kits; fluorescently labeled phalloidin staining was employed to examine the changes in F-actin levels.</p><p><strong>Results: </strong>Coating the cell plates with type I collagen attenuates the senescence of murine hippocampal neuronal HT22 cells and alleviates ferroptosis induced by tert-butyl hydroperoxide (tBHP), a donor of reactive oxygen species. Enhancing ferroptosis-associated signaling by inhibiting GPX4 or FSP1 pathways promotes senescence of HT22 cells, suggesting that the ferroptosis signaling accelerates senescence. Integrin β1, a major component of receptors for collagen, is downregulated in tBHP-treated cells but rescued by collagen. F-actin was markedly disrupted in tBHP-treated cells, while restored by collagen, it protects cells against tBHP-induced ferroptosis and senescence.</p><p><strong>Conclusions: </strong>Our study reveals an F-actin/ferroptosis axis for regulating senescence of HT22 neuronal cells by extracellular type I collagen. The findings here suggest new anti-senescent strategies targeting the F-actin and ferroptosis pathways.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"550-567"},"PeriodicalIF":1.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic cytotoxic effects of glucocorticoid steroids and local anesthetics on human rotator cuff fibroblasts: protective role of N-Acetylcysteine.","authors":"Ju-Yeong Kim, Ra Jeong Kim, Hyung Bin Park","doi":"10.1080/03008207.2026.2710855","DOIUrl":"10.1080/03008207.2026.2710855","url":null,"abstract":"<p><strong>Purpose: </strong>Steroid injections are commonly used for the treatment of tendinopathy, often in combination with local anesthetics. However, both agents may exert cytotoxic effects on tendon cells. This study aimed to investigate the synergistic cytotoxic effects of glucocorticoid steroids and local anesthetics on human rotator cuff fibroblasts (RCFs) and to evaluate the potential protective role of N-acetylcysteine (NAC), an antioxidant.</p><p><strong>Methods: </strong>Human RCFs were treated with individual glucocorticoid steroids or local anesthetics, their combinations, and NAC pretreatment. Cell viability was assessed using MTT and Live/Dead assays. Apoptosis was evaluated by Annexin V/propidium iodide staining and TUNEL assays. Intracellular reactive oxygen species (ROS) generation was measured using the DCF-DA assay, and the expression of apoptosis-related proteins was analyzed by Western blotting.</p><p><strong>Results: </strong>Both glucocorticoid steroids and local anesthetics reduced cell viability in a time- and concentration-dependent manner. Their combined administration produced a synergistic increase in cytotoxicity, intracellular ROS generation, and apoptotic markers, including cleaved caspase-3 and poly (ADP-ribose) polymerase (PARP). Among the combinations tested, methylprednisolone plus lidocaine induced the greatest cytotoxicity, whereas combinations containing ropivacaine showed the lowest toxicity. NAC pretreatment significantly attenuated cytotoxicity, ROS generation, and apoptosis.</p><p><strong>Conclusions: </strong>Glucocorticoid steroids and local anesthetics synergistically induce apoptosis in human rotator cuff fibroblasts through oxidative stress. Pretreatment with NAC effectively attenuates these cytotoxic effects, suggesting that NAC may serve as a promising protective strategy to improve the safety of steroid and local anesthetic injections in the treatment of tendinopathy.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"524-538"},"PeriodicalIF":1.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study on the detection of synovial matrix stiffness in mice with osteoarthritis and its impact on the expression of RAB27A in synovial fibroblasts.","authors":"Jin Kaiyuan, Li Hanglin, Deng Hong, Dong Yilei, Hou Boyao, Deng Yaxin","doi":"10.1080/03008207.2026.2706656","DOIUrl":"10.1080/03008207.2026.2706656","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the changes in synovial matrix stiffness in a mouse model of osteoarthritis (OA) and the expression of RAB27A, a key regulator of exosome biosynthesis, in synovial fibroblasts, and to validate the effect of matrix stiffness on RAB27A expression in vitro.</p><p><strong>Methods: </strong>OA was induced in mouse knees by anterior cruciate ligament transection combined with medial meniscus destabilization (ACLT+DMM). Modeling efficacy was confirmed by Micro-CT, histology, and immunofluorescence. Synovial matrix stiffness was assessed by using nanoindentation. Mouse synovial fibroblasts were cultured on PEGDMA hydrogels with different stiffness, and RAB27A expression was detected by westernblot.</p><p><strong>Results: </strong>Compared with the control group, the OA group exhibited a significant increase in synovial Young's modulus (~64%, <i>p</i> < 0.05), along with a ~ 1.53 fold increase in RAB27A-positive cells (<i>p</i> < 0.001). RAB27A expression showed a strong positive correlation with matrix stiffness (<i>r</i> = 0.671, <i>p</i> < 0.01). In vitro, the expression of RAB27A, MMP13, and COX2 was significantly upregulated in synovial fibroblasts cultured on stiff PEGDMA hydrogels, confirming a direct regulatory effect of matrix stiffness on exosome-related protein expression.</p><p><strong>Conclusions: </strong>Increased synovial matrix stiffness in OA may upregulate RAB27A expression, potentially regulating exosome secretion in synovial fibroblasts. This reveals a novel mechano-biological coupling mechanism in OA synovitis.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"499-508"},"PeriodicalIF":1.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory crosstalk between rotator cuff tissues is altered with age and sex.","authors":"Hana Kalčo, Paola Divieti Pajevic, LaDora V Thompson, Brianne K Connizzo","doi":"10.1080/03008207.2026.2723146","DOIUrl":"10.1080/03008207.2026.2723146","url":null,"abstract":"<p><strong>Purpose: </strong>Musculoskeletal disorders, particularly those affecting the shoulder, are a significant health concern in aging populations. Nevertheless, the initiating factors of joint degeneration remain poorly understood. Research has primarily focused on age-related changes in individual musculoskeletal tissues, with limited investigation into the complex interactions between tissues. Recent studies on communication between musculoskeletal tissues and other organs have gained attention, but local interactions within the shoulder remain underexplored. This study aims to investigate age- and sex-related differences in bone-tendon-muscle crosstalk, hypothesizing that these interactions vary by age and sex, with older and female tissues exhibiting a reduced secretory phenotype.</p><p><strong>Methods: </strong>Using novel in vitro monoculture and co-cultures of explanted whole tissues, we assessed inflammatory responses across bone, tendon, and muscle from young and aged male and female C57BL/6J mice.</p><p><strong>Results: </strong>Our results demonstrate significant age- and sex-dependent differences in cytokine secretion, with aged males and females showing altered inflammatory profiles. We observed a general increase in pro-inflammatory cytokine secretion in monocultures, with aging amplifying this response. Tissue co-cultures revealed that crosstalk between bone and tendon was primarily mediated through secreted factors, while muscle-tendon communication required physical proximity or contact, suggesting a distinct mode of interaction between these tissues. Sex differences were evident in both the individual tissue responses and in the patterns of inter-tissue communication. However, these sex differences diminished with aging, indicating that the age-related decline in tissue-specific signaling may override sex-based distinctions.</p><p><strong>Conclusions: </strong>Our findings suggest that tendon plays a crucial role in mediating inter-tissue communication, with aging disrupting this crosstalk in a sex-dependent manner.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"598-607"},"PeriodicalIF":1.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osteoclast-lineage Indian hedgehog sustains RANKL-induced osteoclastogenesis and bone resorption via the JNK/c-Fos/NFATc1 axis during postnatal bone remodeling.","authors":"Jian Sun, Siqian Liu, Xinle Che, Jiaju Yang, Yueyao Li, Zhengquan Dong, Pengcui Li, Li Guo, Xiaochun Wei, Chongwei Chen, Lei Wei, Yunfei Wang","doi":"10.1080/03008207.2026.2705417","DOIUrl":"10.1080/03008207.2026.2705417","url":null,"abstract":"<p><strong>Purpose: </strong>Bone remodeling depends on the coordinated balance between osteoclast-mediated resorption and osteoblast-mediated formation. Although Indian hedgehog (Ihh) is known to regulate skeletal development and bone homeostasis, its direct involvement in osteoclastogenesis remains unclear.</p><p><strong>Methods: </strong>We generated a novel mouse model, Ctsk-Cre^ERT2; Ihh^fl/fl, to investigate the role of Ihh in osteoclast lineage cells. Skeletal phenotypes were assessed by radiography, micro-CT, histology, dynamic histomorphometry, and three-point bending tests. Bone marrow macrophages were isolated to assess osteoclast precursor viability, RANKL-induced osteoclast differentiation, F-actin ring formation, and bone resorptive activity using CCK-8 assays, TRAP staining, phalloidin staining, and resorption pit assays. Osteoclastogenic gene expression and signaling pathway activation were examined by RT-qPCR and Western blotting.</p><p><strong>Results: </strong>Ihh^CKO mice exhibited reduced body weight and an osteosclerotic phenotype, characterized by increased metaphyseal trabecular bone mass, improved femoral peak load and stiffness, and reduced cortical bone parameters. Histological analyses revealed fewer TRAP-positive osteoclasts on trabecular surfaces, increased osteoblast-related parameters, and decreased cortical bone formation indices. In vitro, Ihh deficiency reduced osteoclast precursor viability, impaired RANKL-induced osteoclast formation, decreased F-actin ring number/size and nuclei per osteoclast, and markedly reduced resorption pit formation. Mechanistically, Ihh loss suppressed osteoclast marker and fusion-related genes and diminished RANKL-induced JNK phosphorylation, c-Fos, NFATc1, and CTSK expression.</p><p><strong>Conclusions: </strong>Osteoclast-lineage-derived Ihh is required for efficient RANKL-induced osteoclastogenesis and bone resorption, at least in part by sustaining the JNK/c-Fos/NFATc1 axis. These findings identify Ihh as an osteoclast-intrinsic regulator of postnatal bone remodeling.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"480-498"},"PeriodicalIF":1.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic comparison of the infrapatellar fat pad between young patients with traumatic knee injury and older patients with knee osteoarthritis.","authors":"Tao Li, Pan Wang, Chun Li, Yifan Chen","doi":"10.1080/03008207.2026.2712531","DOIUrl":"10.1080/03008207.2026.2712531","url":null,"abstract":"<p><strong>Purpose: </strong>The infrapatellar fat pad (IFP) is increasingly recognized as an active contributor to knee osteoarthritis (KOA) pathogenesis. However, age-related transcriptional changes in the IFP remain poorly understood, and whether observed differences are purely age-dependent or confounded by disease status is unclear. This study aimed to compare transcriptomic profiles of the IFP between young patients with traumatic knee injury and older patients with KOA.</p><p><strong>Methods: </strong>IFP samples were obtained from three young trauma patients (21-28 years, KL grade 0) and three older patients with KOA (64-72 years, KL grade III-IV). Bulk RNA sequencing was performed to compare transcriptomes between groups. Differential expression was analyzed with DESeq2 (|log2FC| ≥1, unadjusted <i>p</i> < 0.05), followed by GO and KEGG pathway enrichment. Real-time PCR confirmed key expression changes.</p><p><strong>Results: </strong>Compared with the young trauma group, the old KOA group exhibited 247 upregulated (<i>CSN1S1</i>, <i>SCN9A</i>, <i>P2RY14</i>, <i>EIF3C</i>, etc) and 334 downregulated genes (<i>PI15</i>, <i>WISP3</i>, <i>DMKN</i>, <i>NUTM2G</i>, etc). The old KOA group exhibited significantly reduced expression of extracellular matrix (ECM) genes, including <i>COL1A1</i>, <i>COL2A1</i>, and <i>FN1</i>. Additionally, core genes of the PI3K-Akt signaling pathway, such as <i>AKT1</i>, <i>ITGA2B</i>, and <i>MYB</i>, were also downregulated in the old KOA group.</p><p><strong>Conclusions: </strong>The IFP in old KOA exhibits a transcriptomic profile characterized by dampened ECM structural gene expression and suppressed PI3K-Akt signaling compared with young trauma patients. While confounded by injury status, these findings suggest that age-related loss of ECM integrity may contribute to IFP dysfunction in established KOA and warrant validation in healthy aging cohorts.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"568-582"},"PeriodicalIF":1.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination ex vivo regional gene therapy with sonic hedgehog and bone morphogenetic protein-2 does not enhance bone healing in critical size defects.","authors":"Cory K Mayfield, Julian Wier, Jacob R Ball, Matthew C Gallo, Fergui Hernandez, Tara Shelby, Elizabeth Lechtholz-Zey, Sarah Bergren, Hannah Shelby, Amy Tang, Osamu Sugiyama, Jay R Lieberman","doi":"10.1080/03008207.2026.2697221","DOIUrl":"10.1080/03008207.2026.2697221","url":null,"abstract":"<p><strong>Purpose: </strong>Large bone defects pose significant challenges for orthopedic surgeons. Regional gene therapy using adipose-derived stem cells (ADSCs) transduced with a lentiviral vector to express bone morphogenetic protein 2 (LV-BMP-2) has shown promise in preclinical models. Recent studies suggest sonic hedgehog (SHH)-mediated signaling may act synergistically with BMP-2 to enhance osteogenesis. This study evaluated whether combination gene therapy with rat ADSCs transduced with LV-BMP-2 and LV-SHH could heal rat critical size femoral defects.</p><p><strong>Methods: </strong>Seventy-one rats were randomly assigned to seven groups including four experimental groups, one positive control, and two negative controls. A two-step transcription amplification (TSTA) lentiviral vector was used to transduce BMP-2 and/or SHH into ADSCs. A 6 mm critical-sized femoral defect was created in Lewis rats and experimental groups received transduced cells. Biomechanical, imaging, and histomorphometric analysis was conducted to evaluate bone healing outcomes.</p><p><strong>Results: </strong>No significant difference in mean stiffness, total energy to failure, or maximum torque was observed between rats receiving 3 M LV-BMP-2 versus those receiving combination therapy of 3 M or 5 M LV-BMP-2 + LV-SHH therapy, however all had superior healing compared to negative controls. Similar results were observed for imaging and histomorphometric outcomes.</p><p><strong>Conclusions: </strong>These results demonstrate that combination gene therapy with LV-BMP-2+LV-SHH results in equivalent healing when compared to BMP-2 therapy at the same cell dose, demonstrating that SHH does not enhance osteoinductive signaling <i>in vivo</i> when using this therapeutic strategy. These findings suggest that the regenerative capacity of regional LV-BMP-2 gene therapy may exceed the window in which SHH can provide incremental biological benefit.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"467-479"},"PeriodicalIF":1.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanotransduction in musculoskeletal mesenchymal tissues: implications for bone, tendon, and cartilage regenerative engineering-a narrative review.","authors":"Nahum Rosenberg","doi":"10.1080/03008207.2026.2729285","DOIUrl":"10.1080/03008207.2026.2729285","url":null,"abstract":"<p><strong>Purpose: </strong>To integrate evidence on how mechanical signals regulate musculoskeletal connective-tissue biology and how cellular context and loading history shape mechanotransduction and mechanical memory.</p><p><strong>Methods: </strong>This narrative review synthesized PubMed-indexed evidence on extracellular matrix mechanics, adhesion complexes, the cytoskeleton, nucleus, primary cilia, mechanosensitive ion channels, cell state, and loading history in bone, tendon, ligament, and cartilage.</p><p><strong>Results: </strong>Mechanotransduction is best understood as a coupled extracellular matrix-integrin-cytoskeleton-nucleus continuum rather than as independent cytoskeletal or nuclear drivers. Responses are conditioned by lineage stage, anatomic niche, inflammation, cellular subpopulation, and prior mechanical exposure. Mechanical memory may be encoded through persistent YAP/TAZ activity, microRNA programs, DNA methylation, histone modifications, chromatin architecture, and metabolic remodeling. Evidence is strongest for bone, including Piezo-dependent osteogenesis, TRPV4-mediated shear sensing, viscoelastic compression, osteocyte-stromal extracellular-vesicle signaling, and osteogenesis-angiogenesis coupling. Tendon and ligament require anisotropic architecture and strain-window control, whereas cartilage shows a narrow distinction between physiologic TRPV4-associated anabolism and high-strain or inflammation-sensitized Piezo/YAP-mediated maladaptation.</p><p><strong>Conclusions: </strong>Translational implications include mechanically defined cell expansion, biomaterial preconditioning, stage-specific rehabilitation, and potency assays incorporating loading history. Direct clinical validation of stable perioperative cellular mechanical memory remains limited. Future studies should combine controlled mechanical perturbation with bulk and single-cell RNA sequencing, chromatin-accessibility profiling, spatial methods, and perturbational genomics.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"628-641"},"PeriodicalIF":1.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kaempferol binds with NSUN2 to mediate RNA 5-methylcytosine modification of BMP2 in osteogenic differentiation.","authors":"Nan Yu, Guanyi He, Rui Huang, Yingzhe Jin, Ming Yao, Huibin Zhang, Rui Zhu","doi":"10.1080/03008207.2026.2669838","DOIUrl":"10.1080/03008207.2026.2669838","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to investigate the effects and underlying mechanism of kaempferol (Kae) on osteogenic differentiation through 5-methylcytosine (m5C) modification in bone metabolism.</p><p><strong>Materials and methods: </strong>Dexamethasone (DEX, 1 μM) was used to inhibit the differentiation of MC3T3-E1 cells to mimic osteoporosis <i>in vitro</i>. The effects of Kae (5, 10, and 20 μM) on osteogenic differentiation were evaluated. m5C levels in MC3T3-E1 cells were measured by m5C dot blot assay, and the expression of several m5C-related genes was detected. The binding between Kae and an m5C-related gene was examined, and the interaction between NSUN2 andBMP2 was assessed. To investigate the regulatory role of Kae in osteoporosis, an ovariectomy (OVX)-induced osteoporotic mouse model was established.</p><p><strong>Results: </strong>Kae at 5-20 μM promoted osteogenic differentiation of MC3T3-E1 cells. Kae treatment increased m5C levels and NSUN2 expression in MC3T3-E1 cells. Kae bound to NSUN2, and inhibition of NSUN2 partially attenuated the pro-osteogenic effects of Kae. Furthermore, NSUN2 inhibition promoted BMP2 mRNA degradation. Inhibition of BMP2 significantly reversed the effect of NSUN2 overexpression on osteogenic differentiation. <i>In vivo</i>, Kae alleviated OVX-induced osteoporosis by reducing bone loss.</p><p><strong>Conclusions: </strong>Kae promotes osteogenic differentiation of osteoblasts <i>in vitro</i> and ameliorates bone loss in OVX-induced osteoporotic mice. Kae binds to NSUN2 to mediate RNA m5C modification of BMP2 during osteogenic differentiation. Kae may be a promising therapeutic agent for osteoporosis.</p>","PeriodicalId":10661,"journal":{"name":"Connective Tissue Research","volume":" ","pages":"377-392"},"PeriodicalIF":1.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147866703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}