Bone最新文献

{"title":"Local and systemic immune responses during rhBMP-2 mediated bone regeneration are dose-dependent in rat model of critical-sized bone defect healing.","authors":"Lia K Strait, Lucy Rose, Tyler Guyer, Kimberly A Jones, Graham J DeKeyser, Kaitlyn Link, Dylan Gill, Auveen Hajarizadeh, Kelly E Leguineche, Robert E Guldberg","doi":"10.1016/j.bone.2026.118084","DOIUrl":"https://doi.org/10.1016/j.bone.2026.118084","url":null,"abstract":"<p><p>Bone morphogenetic proteins (BMPs) are among the most potent clinical therapeutics for promoting bone regeneration, yet their use is limited by potential adverse events such as heterotopic bone formation, osteolysis, and soft tissue inflammation. Sustained release delivery systems may reduce the minimum effective BMP dose needed to induce functional bone healing but have yet to be fully characterized or translated to clinical use. Here, we utilized a rat model of segmental femur defect healing to investigate the dose-dependent inflammatory effects of BMP delivery in a hydrogel-based system by profiling local and systemic immune responses. Defects were treated with the delivery vehicle only (control), a minimum effective dose of BMP-2, or a high dose of BMP-2. The minimum effective BMP-2 dose induced comparable bone formation within the defects but significantly less ossification outside the defect region relative to the high dose. Immune profiling revealed significant dose-dependent effects of BMP-2 delivery on cellular and proteomic signatures both locally and systemically. Notably, however, no significant differences in immune response markers were detected between the vehicle only control and minimum effective dose groups at any timepoint. This study confirms that BMP-2 delivered at high doses incites strong inflammatory responses locally and systemically, but sustained delivery of a minimum effective dose can regenerate bone without provoking bone formation outside the intended delivery location or inflammatory side effects. The results of this study are limited to only two BMP-2 doses and a sustained-release delivery system, and may not remain true in the FDA-approved collagen sponge.</p>","PeriodicalId":93913,"journal":{"name":"Bone","volume":" ","pages":"118084"},"PeriodicalIF":3.6,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148898256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paternal age and offspring bone health and body composition at 20 years: Findings from the Raine study.","authors":"Mia A Percival, Kun Zhu, John P Walsh, Marc Sim, Kara B Anderson, Julie A Pasco, Natalie K Hyde","doi":"10.1016/j.bone.2026.118080","DOIUrl":"https://doi.org/10.1016/j.bone.2026.118080","url":null,"abstract":"<p><strong>Aims: </strong>There is growing evidence supporting paternal contributions to child health. Previous findings from the Vitamin D In Pregnancy study suggest that advanced paternal age is associated with a range of poorer bone measures for offspring at age 11 years. Whether these associations are evident when peak bone mass is attained remains unknown. This study aimed to investigate associations between paternal age and offspring bone health and body composition at age 20 years.</p><p><strong>Methods: </strong>Data from the Raine study, a multigenerational cohort, were used. Among 1183 offspring with total body DXA data (Norland XR-36 densitometer) at the 20-year follow up, 1142 with information on their father's age were included in this analysis. Linear regression and restricted cubic spline models were developed to examine associations of offspring bone and body composition outcomes at 20 years and paternal age during pregnancy (16-20 weeks' gestation).</p><p><strong>Results: </strong>Fathers' mean age was 31 years (SD 6.6, range 15-58). Restricted cubic spline models adjusted for sex, maternal, paternal and offspring factors revealed complex, nonlinear associations between paternal age and total body bone mineral density (BMD) and content (BMC). Offspring of fathers in the lowest quartile (Q1) of paternal age (median age 25 years) had between 0.018 g/cm² to 0.023 g/cm² higher BMD (1.7-2.1%) than those in Q2 (median age 30 years), Q3 (33 years) and Q4 (39 years) and between 61 g and 67 g (2.1-2.3%) higher BMC than those of Q2 and Q3. Paternal age was not significantly associated with offspring total body lean or fat mass in linear regression models.</p><p><strong>Conclusions: </strong>This study suggests that paternal age in pregnancy is associated with offspring total body bone mass, but not body composition in early adulthood (~20 years). Further confirmatory studies are warranted to better establish the intergenerational effects of paternal age on bone health.</p>","PeriodicalId":93913,"journal":{"name":"Bone","volume":" ","pages":"118080"},"PeriodicalIF":3.6,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148893176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated analysis of human osteocyte lacunar ultrastructure and bone proteome profiling reveals coupling between immune and osteogenic signaling pathways.","authors":"Sjur Reppe, Liebert P Nogueira, Fangtang Yu, Haldor Valland, Vidis T Gautvik, Tor P Utheim, Yi-Hsiang Hsu, Janne E Reseland, Kaare M Gautvik","doi":"10.1016/j.bone.2026.118077","DOIUrl":"https://doi.org/10.1016/j.bone.2026.118077","url":null,"abstract":"<p><p>Osteocytes reside within lacunae where they sense mechanical loading and regulate bone formation and resorption. Although lacunae define the osteocyte population, their number and volume are themselves regulated, and evidence regarding lacunar structural properties remains inconsistent. The relationship between lacunar ultrastructure and the bone proteome has not previously been explored. We therefore integrated high-resolution ultrastructural and proteomic analyses of femoral bone from osteoporotic patients undergoing hip arthroplasty after fracture (n = 15) and individuals undergoing surgery for osteoarthritis with normal or near-normal bone mineral density (n = 42). Lacunar morphology was assessed using high-resolution micro-computed tomography, and proteomic profiling was performed by liquid chromatography-tandem mass spectrometry, quantifying approximately three thousand proteins. Lacunar density and total lacunar volume normalized to bone volume were inversely correlated with total hip bone mineral density T-score (r = -0.462 and r = -0.471), indicating increased lacunar number and total lacunar volume in osteoporotic bone. In both sexes, lacunar density correlated strongly with total lacunar volume per bone volume (males: r = 0.69, p = 1.2 × 10^-6; females: r = 0.70, p = 1.1 × 10^-3), demonstrating tight coupling between lacunar number and volume. Exploratory pathway enrichment analysis revealed enrichment of pathways related to ROBO receptor signaling, translational regulation, and complement-mediated inflammatory processes. These findings link osteocyte lacunar ultrastructure to the bone proteome and identify osteocytes as central regulators integrating immune signaling, mechanosensing, and bone turnover.</p>","PeriodicalId":93913,"journal":{"name":"Bone","volume":" ","pages":"118077"},"PeriodicalIF":3.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meis2 transcription factor regulates craniofacial osteogenesis via IGF signaling and cell adhesion.","authors":"Erika Hudacova, Daniel Zucha, Mehmet Mahsum Kaplan, Ondrej Machon","doi":"10.1016/j.bone.2026.118075","DOIUrl":"10.1016/j.bone.2026.118075","url":null,"abstract":"<p><p>Cranial neural crest cell (cNCC)-derived mesenchyme must precisely integrate intrinsic transcriptional programs with localized signaling cues to orchestrate craniofacial skeletogenesis. While the transcription factor Meis2 is an essential regulator of this process, the spatially defined cellular contexts and downstream effector pathways remain poorly characterized. Building upon previous single-cell transcriptomic evidence of Igf2 dysregulation, we employed spatial transcriptomics integrated with single-cell references to map the mesenchymal landscape in Meis2-deficient embryos during early ossification. This spatial mapping identified distinct chondro-osteoprogenitor niches and revealed a significant enrichment of the IGF2 signaling axis within mutant mesenchymal compartments. We validated these spatial expression patterns in vivo, confirming the localized upregulation of Igf2 in Meis2-deficient osteo-chondroprogenitors. Functional in vitro assays demonstrated that IGF signaling is a potent modulator of cNCC-derived mesenchymal differentiation. Exogenous IGF2 enhanced osteogenic potential, whereas inhibition of the IGF1 receptor (IGF1R) significantly attenuated osteogenesis as measured using ALP activity. Furthermore, the impaired bone formation in Meis2 mutants correlated with disrupted cell adhesion dynamics. Collectively, these findings establish the importance of IGF2 signaling during embryonic craniofacial ossification and provide a mechanistic link between Meis2 loss, altered cell adhesion, and dysregulated osteogenic differentiation.</p>","PeriodicalId":93913,"journal":{"name":"Bone","volume":" ","pages":"118075"},"PeriodicalIF":3.6,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148868521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NOTCH3 disrupts the osteoblast transcriptome in femoral bone of 1-month-old male C57BL/6 mice.","authors":"Ernesto Canalis, Lauren Schilling, Emily Denker","doi":"10.1016/j.bone.2026.118074","DOIUrl":"10.1016/j.bone.2026.118074","url":null,"abstract":"<p><p>Notch signaling plays a fundamental role in skeletal physiology, and activation of NOTCH3 in osteoblasts/osteocytes impairs corticalization, causes cortical osteopenia and suppresses cancellous bone remodeling. To address possible mechanisms responsible, we explored transcriptome profiles in osteocytes and femoral bone from 1-month-old male C57BL/6 mice following activation of NOTCH3 in Dmp1-expressing cells. We used a NOTCH3 gain-of-function mouse line expressing the NOTCH3 intracellular domain (N3ICD) from the Rosa26 locus (R26-N3ICD mice) following the deletion of a loxP flanked STOP cassette, which was accomplished by crossing R26-N3ICD mice with Dmp1-Cre transgenics. Bulk RNA-Sequencing (RNA-Seq) of osteocytes revealed that expression of the N3ICD enhanced pathways associated with rheumatoid arthritis signaling, osteoclast differentiation, collagen degradation and the immune response. Single cell (sc)RNA-Seq of femoral bone from 1-month-old mice revealed clusters of cells related to vascular and osteogenic cells. Trajectory analysis showed a close association among selected clusters in control and N3ICD-expressing femurs. There were modest differences between N3ICD-expressing and control cells in cluster allocation, except for a decrease in the osteogenic cluster in N3ICD-induced cells. Analysis of intron/exon sequences demonstrated that NOTCH3 altered the velocity of the osteogenic cluster. In conclusion, NOTCH3 enhances the activity of selected pathways including osteoclast differentiation and suppresses the transcription of osteogenic cells in femoral bone.</p>","PeriodicalId":93913,"journal":{"name":"Bone","volume":" ","pages":"118074"},"PeriodicalIF":3.6,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148868531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The association between resting autonomic nervous system activity and bone mineral density in older adults.","authors":"Jayde A Collier, Belinda R Beck, Surendran Sabapathy, Tyler Collings, Benjamin K Weeks","doi":"10.1016/j.bone.2026.118073","DOIUrl":"10.1016/j.bone.2026.118073","url":null,"abstract":"<p><strong>Background: </strong>Elevated sympathetic nervous system activity has been shown to have a detrimental effect on bone mass in animal studies, whereas parasympathetic activity is thought to exert a protective effect. However, little is known about the relationship between autonomic nervous system activity and bone health in humans. This study aimed to investigate the relationship between resting autonomic nervous system activity and areal BMD (aBMD) or volumetric BMD (vBMD) in older adults.</p><p><strong>Methods: </strong>A total of 119 older adults (27 men, 92 women) were included in this cross-sectional study. Participants underwent DXA scans of the left hip and lumbar spine (L1-4) as well as, pQCT scans at the 4% and 38% left tibia sites. Sympathetic activity was evaluated using non-invasive skin sympathetic nerve activity and galvanic skin response. Parasympathetic activity was evaluated using time-domain and frequency-domain heart rate variability metrics. Multiple linear regression models adjusted for sex, age, lifetime bone-relevant physical activity and BMI, were used to examine associations between resting sympathetic and parasympathetic nervous system activity and BMD (primary analysis) or vBMD (secondary analysis). P values were adjusted using the Benjamini-Hochberg procedure to control the false discovery rate (FDR).</p><p><strong>Results: </strong>None of the primary aBMD associations were significant following FDR correction. Higher integrated skin sympathetic nerve activity burst area was negatively associated with total hip aBMD before correction (β = -0.214, P = 0.008; FDR-adjusted P = 0.062). In the secondary analysis, the skin conductance response frequency was negatively associated with trabecular vBMD at the 4% tibial site (β = -0.354, P = 0.001; FDR-adjusted P = 0.004). Parasympathetic nerve activity was not associated with aBMD or vBMD.</p><p><strong>Conclusion: </strong>The primary aBMD hypotheses were not supported following correction for multiple comparisons. Exploratory associations between elevated sympathetic activity and lower areal and volumetric BMD warrants further investigation as a factor in age-related bone loss.</p>","PeriodicalId":93913,"journal":{"name":"Bone","volume":" ","pages":"118073"},"PeriodicalIF":3.6,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148851994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"External validation of a deep-learning based automatic contouring algorithm for the radius and tibia on first- and second-generation HR-pQCT scans.","authors":"F J P N van den Bergh, B van Rietbergen, J P van den Bergh, E Biver, C E Wyers, M S A M Bevers","doi":"10.1016/j.bone.2026.118076","DOIUrl":"10.1016/j.bone.2026.118076","url":null,"abstract":"<p><p>Current contouring software for high-resolution peripheral quantitative CT (HR-pQCT) requires manual correction, which can be subjective and time-consuming. In this study, we externally validated a deep learning (DL) model for automatic periosteal and endosteal contouring in second-generation HR-pQCT scans of the distal radius and tibia. Additionally, we compared the DL model's contours with uncorrected standard automatic periosteal and endosteal HR-pQCT contours (AUTO) in second-generation HR-pQCT scans and evaluated its performance in first-generation HR-pQCT scans. In 939 second-generation HR-pQCT scans, median Dice (DSC) and Jaccard (JSC) similarity coefficients for periosteal and endosteal DL contours were >0.92 and median average (ASSD) and maximum (HD) symmetric surface distances <1.15 mm when compared with our reference contours (AUTO with manual periosteal correction). Most HR-pQCT parameters differed significantly when comparing DL and reference contours, but differences were small (median between -0.6% and +6.6%) and correlations high (>0.78). Comparison with AUTO gave considerably larger maximum HDs and differences in HR-pQCT parameters - predominantly due to erroneous AUTO contours. In 300 first-generation HR-pQCT scans, median DSC and JSC were >0.98 and median ASSD and HD <0.49 mm when comparing periosteal DL contours with manually-guided snake-based periosteal contours (SNAKE). Most HR-pQCT parameters from standard morphological and extended cortical analysis differed significantly when comparing periosteal DL and SNAKE contours combined with standard automatic endosteal contours, but differences were small (median between -1.2% and +4.1%) and correlations high (>0.95). To conclude, the DL model performed well for automatic periosteal and endosteal contouring on second-generation HR-pQCT and for automatic periosteal contouring on first-generation HR-pQCT.</p>","PeriodicalId":93913,"journal":{"name":"Bone","volume":" ","pages":"118076"},"PeriodicalIF":3.6,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148852004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of trabecular microstructure using photon-counting CT: Influence of dose, spatial resolution and reconstruction algorithms.","authors":"Jaime A Peña, Felix Thomsen, Timo Damm, Sandra Freitag-Wolf, Matthias Frölich, Stefan O Schönberg, Heinz-Peter Schlemmer, Klaus Engelke, Claus-Christian Glüer, Jan-Bernd Hövener, Olav Jansen, Marc Kachelrieß, Stefan Sawall","doi":"10.1016/j.bone.2026.118066","DOIUrl":"https://doi.org/10.1016/j.bone.2026.118066","url":null,"abstract":"<p><strong>Purpose: </strong>Photon-counting CT (PCCT) for quantitative microstructural assessments of the central skeleton remains underexplored. This study evaluated the effects of radiation dose, spatial resolution, noise and reconstruction algorithm on bone mineral density (BMD), bone volume fraction (BV/TV), and trabecular separation (Tb.Sp).</p><p><strong>Materials and methods: </strong>Seven excised human vertebral bodies embedded in polymethylmethacrylate were scanned using a clinical PCCT scanner (Naeotom Alpha, Siemens Healthineers): natively at (20 mGy CTDI_{32 cm}) and within a thorax phantom at (6, 9, 12 and 15 mGy). Four repeated scans (15 mGy) served as reference. Filtered back projection (FBP) and iterative (QIR3) reconstructions were used with Br56u, Br76u and Br89u kernels. Bone parameters were estimated from cancellous volumes. Differences were tested with Wilcoxon signed-rank tests. Radiation dose impact was assessed using Bland-Altman analysis and Lin's concordance coefficient (rccc).</p><p><strong>Results: </strong>Median (IQR) ranges for BMD were 177.5 (55.1)-191.9 (57.5) mgHA/cm³, for BV/TV 0.25 (0.20)-0.47 (0.05), and Tb.Sp 0.29 (0.02)-1.50 (1.64) mm. FBP consistently yielded higher BMD and BV/TV than QIR3, albeit non-significant after statistical correction. BMD differences between algorithms were 6.6 mgHA/cm³ at 6.0 mGy Br89u, and 0.1 mgHA/cm³ for Br76u at 20 mGy. Noise was higher in FBP (range: 13-470 HU) vs QIR3 (6-124 HU). The mean absolute (%) differences to the reference across dose levels were best for Br76u/QIR3 (BMD: 0.83 mgHA/cm³ (0.5%); BV/TV: 0.01 (2.6%) and Tb.Sp: 0.79 mm (18%)). Best robustness against radiation dose changes was observed with Br56u/QIR3 and Br76u/QIR3.</p><p><strong>Conclusions: </strong>Br56u showed enlarged Tb.Sp levels despite excellent agreement, while Br89u showed increased noise levels and instability. Br76u/QIR3 showed the best balance between microstructural accuracy, image noise and stability at clinically diagnostic dose levels, for example 15 mGy CTDIvol.</p>","PeriodicalId":93913,"journal":{"name":"Bone","volume":" ","pages":"118066"},"PeriodicalIF":3.6,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZCCHC4-mediated m6A methylation regulates the UHRF1/CDO1 axis to inhibit ferroptosis and promote osteosarcoma malignant progression.","authors":"Kai Song, Ju Liu, Bowen Han, Rui Liu, Huazhang Zhong, Dasheng Tian","doi":"10.1016/j.bone.2026.118070","DOIUrl":"10.1016/j.bone.2026.118070","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Osteosarcoma (OS) represents a common primary malignant bone tumor associated with unfavorable clinical outcomes. Growing evidence underscores the crucial involvement of N6-methyladenosine (m6A) modifications in tumor development, but the specific mechanisms underlying the m6A regulatory network in OS remain to be elucidated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Potential key target genes in OS were identified through bioinformatic analyses, followed by the characterization of m6A-related regulatory proteins, specifically, writer and reader proteins, which showed significant associations with these targets. To elucidate the mechanistic role of m6A methylation in regulating UHRF1 expression, a series of in vitro assays were conducted. These included RNA pull-down, MeRIP-PCR, dot blot, dual-luciferase reporter assays, and RNA stability assays, which collectively confirmed the interaction between m6A regulatory proteins and UHRF1 mRNA. For functional investigations, OS cell lines (U2OS, Saos2, and 143B) with gene silencing or overexpression were established, and the role of UHRF1 in cellular proliferation, migration, and invasion was assessed using CCK-8 assays, Transwell migration and invasion assays, flow cytometry, and wound healing assays. In addition, GSH/GSSG ratio, Fe&lt;sup&gt;2+&lt;/sup&gt; concentration, and ROS levels were measured using commercial assay kits to explore ferroptosis-related functional mechanisms. To validate the in vivo relevance of our findings, a xenograft mouse model was established. Finally, functional rescue experiments were performed to mechanistically confirm the critical role of the ZCCHC4-UHRF1-CDO1 regulatory axis in OS progression.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;ZCCHC4, functioning as an m6A methyltransferase, enhances the stability of UHRF1 mRNA by catalyzing its m6A modification, thereby promoting increased expression of UHRF1. In parallel, IGF2BP3, an established m6A reader protein, specifically recognizes and binds to the m6A-modified sites on UHRF1 mRNA, further stabilizing the transcript and modulating its downstream biological functions. METTL3/METTL14 knockdown experiments ruled out the contribution of classical m6A methyltransferases, confirming that ZCCHC4 is the primary methyltransferase for UHRF1. Dual-luciferase assays and bisulfite sequencing revealed that UHRF1 suppresses CDO1 transcription by inducing high methylation of its promoter, thereby reducing ROS/Fe&lt;sup&gt;2+&lt;/sup&gt; levels and increasing GSH, which in turn blocks ferroptosis. In U2OS, Saos2, and 143B cells, silencing UHRF1 or ZCCHC4 inhibited proliferation, migration, and invasion while activating ferroptosis. Overexpression of UHRF1 had the opposite effect. In vivo models confirmed that UHRF1 silencing inhibited tumor growth. Furthermore, UHRF1 overexpression partially reversed the phenotypes induced by ZCCHC4 knockdown.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;In summary, this study reveals for the first time the complete molecul","PeriodicalId":93913,"journal":{"name":"Bone","volume":" ","pages":"118070"},"PeriodicalIF":3.6,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of bone fracture following saccharated ferric oxide in Japan.","authors":"Kosuke Iwasaki, Masakazu Terauchi, Myles Wolf","doi":"10.1016/j.bone.2026.118056","DOIUrl":"10.1016/j.bone.2026.118056","url":null,"abstract":"<p><p>Intravenous (IV) iron is recommended for the treatment of iron deficiency anemia (IDA) when oral iron is ineffective or poorly tolerated, or when rapid iron replenishment is needed. However, specific IV iron formulations, including saccharated ferric oxide (SFO) and ferric carboxymaltose (FCM), are associated with increased rates of hypophosphatemia and subsequent osteomalacia. Clinical trials of these IV iron formulations were not sufficiently large or long enough to assess whether these effects translate into increased risk of fracture. This observational cohort study used claims data from a Japanese health insurance database between June 2018 and May 2021 to assess the risk of fracture following treatment with SFO in patients with IDA who were propensity score-matched (approximately 4:1) to controls who had anemia but were not treated with IV iron. Since kidney dysfunction partially protects against severe IV iron-induced hypophosphatemia, a secondary analysis was restricted to patients with normal kidney function. Of the patients treated with SFO, 29,037 were matched to 128,311 untreated controls. Treatment with SFO was associated with significantly higher risk of incident fracture compared with controls (hazard ratio [HR]: 1.154; 95% confidence interval [CI]: 1.088, 1.225; p < 0.0001). In patients with normal kidney function, the risk of fracture was increased in those who received higher cumulative doses of SFO. Patients with kidney dysfunction were also at significantly increased risk of fracture following SFO (HR: 1.512; 95% CI: 1.344, 1.702; p < 0.0001). These real-world data suggest that SFO, known to cause significant hypophosphatemia, also increases the risk of fracture.</p>","PeriodicalId":93913,"journal":{"name":"Bone","volume":" ","pages":"118056"},"PeriodicalIF":3.6,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}