Bone最新文献

{"title":"Chronic kidney disease- mineral and bone disorder in autosomal dominant policystic kidney disease","authors":"S. Lai ,&nbsp;A.M. Perrotta ,&nbsp;L. Tartaglione ,&nbsp;D. Mastroluca ,&nbsp;F. Tinti ,&nbsp;P. Menè ,&nbsp;M. Pasquali ,&nbsp;P.M. Ferraro ,&nbsp;S. Mazzaferro ,&nbsp;S. Rotondi","doi":"10.1016/j.bone.2025.117652","DOIUrl":"10.1016/j.bone.2025.117652","url":null,"abstract":"<div><div>Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder characterized by bilateral renal cysts that detach from parental tubules, progressively leading to renal function loss. Patients with ADPKD represent a unique subset of chronic kidney disease (CKD) individuals, sharing common CKD features while also exhibiting distinct traits specific to ADPKD. This review described the unique patterns of mineral and bone disorders present in ADPKD in the early CKD stages. The principal points are: the extraosseous FGF23 production by cystic tissues in the kidneys and liver, resulting in elevated circulating FGF23 levels with possible impact on calcium and phosphate balance and cardiovascular risk in ADPKD; the higher prevalence of low bone turnover disease in ADPKD than in other forms of CKD. This is likely due to disruptions in signals mediated by the Polycystin-1 and Polycystin-2 heterodimers, which are expressed on the primary cilia of osteocytes and osteoblasts, leading to impaired bone anabolism. Given these insights, a comprehensive approach is essential for monitoring and managing mineral and bone disorders in ADPKD patients. Early intervention and targeted therapies could mitigate the progression of mineral and bone disorders and possibly improve patient outcomes.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117652"},"PeriodicalIF":3.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LIPUS promotes osteogenesis via the mcirc_9393-miR-217/326-SIRT1 axis in porous Ti6Al4V scaffolds","authors":"Hongjuan Cao ,&nbsp;Yue Yu ,&nbsp;Lin Wu ,&nbsp;Fengyu Hao","doi":"10.1016/j.bone.2025.117647","DOIUrl":"10.1016/j.bone.2025.117647","url":null,"abstract":"<div><div>The repair of critical-sized bone defects remains a significant clinical challenge. Low-intensity pulsed ultrasound (LIPUS) in conjunction with scaffolds has emerged as a promising therapeutic approach. However, the osteogenic mechanisms of LIPUS combined with porous scaffolds remain incompletely understood, and the osteogenic efficacy requires further enhancement. Here, we investigate the molecular mechanisms underlying mcirc_9393-mediated osteoblastic differentiation and osteogenesis promoted by LIPUS in Ti64 scaffolds. We demonstrate that LIPUS significantly upregulates mcirc_9393 expression, which is critical for LIPUS-induced osteoblast differentiation within Ti64 scaffolds. Mechanistically, mcirc_9393 and miR-217/326, as well as miR-217/326 and sirtuin1 (SIRT1), competitively bind to overlapping miRNA response elements (MREs). Functionally, LIPUS-driven mcirc_9393 upregulation acts as a sponge for miR-217 and miR-326, relieving their inhibitory effects on SIRT1 and promoting osteoblast differentiation. In vivo, mcirc_9393 overexpression enhances scaffold-mediated bone formation under LIPUS stimulation. These findings reveal that LIPUS augments osteogenesis in Ti64 scaffolds via the mcirc_9393/miR-217-326/SIRT1 axis and highlight mcirc_9393 as a potential therapeutic target for improving bone regeneration in LIPUS-scaffold combinatorial therapies.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117647"},"PeriodicalIF":3.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Patient Evidence in XLH (APEX): Baseline analysis of a global data unification program","authors":"Thomas O. Carpenter ,&nbsp;Seiji Fukumoto ,&nbsp;Dieter Haffner ,&nbsp;Erik A. Imel ,&nbsp;Keiichi Ozono ,&nbsp;Haruka Ishii ,&nbsp;Zhiyi Li ,&nbsp;Kerry Sandilands ,&nbsp;Paul Joos-Vandewalle ,&nbsp;Cheuk Lee ,&nbsp;Masanori Kanematsu ,&nbsp;Keith P. McCullough ,&nbsp;Maria Luisa Brandi","doi":"10.1016/j.bone.2025.117649","DOIUrl":"10.1016/j.bone.2025.117649","url":null,"abstract":"<div><h3>Purpose</h3><div>X-linked hypophosphatemia (XLH) is a rare, genetic, progressive, lifelong disorder caused by pathogenic variants in the <em>PHEX</em> gene, leading to excess fibroblast growth factor 23 (FGF23) and renal phosphate wasting. Advancing Patient Evidence in XLH (APEX) is a 10-year global data unification project that combines 3 regional observational studies (XLH Disease Monitoring Program [DMP], International XLH Registry [IXLHR], and SUNFLOWER). APEX aims to describe the burden and lifelong progression of XLH, to collect real-world data on treatment effectiveness and safety, and to investigate regional differences in treatment outcomes.</div></div><div><h3>Methods</h3><div>This was a baseline analysis of the characteristics and disease burden of a global group of patients with XLH.</div></div><div><h3>Results</h3><div>This analysis included 1556 participants (XLH DMP <em>n</em> = 598; IXLHR <em>n</em> = 736; SUNFLOWER <em>n</em> = 222), with 590 participants aged 0–12 years, 193 aged 13–17 years, and 773 aged ≥18 years. Overall, 66 % of participants were female. Family history of XLH and of a <em>PHEX</em> variant were reported for 55 % and 47 % of participants, respectively; 71 % of participants had a confirmed <em>PHEX</em> variant. Participants had reduced height, normal weight, and elevated body mass index compared with a reference population. Clinical histories demonstrated increasing prevalence of dental complications, fractures, and osteoarthritis with age. Median <em>Z</em>-scores for phosphate, tubular maximum reabsorption of phosphate to glomerular filtration rate, and urine calcium/creatinine ratio were below the scores for the reference population.</div></div><div><h3>Conclusion</h3><div>This baseline analysis provides substantial information on the global characteristics and natural history of patients with XLH in the APEX program.</div></div><div><h3>Registration</h3><div><span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> <span><span>NCT03651505</span><svg><path></path></svg></span> (registered August 24, 2018), <span><span>NCT03193476</span><svg><path></path></svg></span> (registered June 13, 2017), <span><span>NCT03745521</span><svg><path></path></svg></span> (registered November 6, 2018).</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117649"},"PeriodicalIF":3.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of a combination of cumulative remnant cholesterol and systemic inflammation on the risk of fragility fracture: A prospective cohort study","authors":"Xiaoli Hou ,&nbsp;Fuyuan Cao ,&nbsp;Nan Zhang ,&nbsp;Lei Xing ,&nbsp;Ning Liu ,&nbsp;Lu Guo ,&nbsp;Shuohua Chen ,&nbsp;Xinhao Fan ,&nbsp;Wenchao Yao ,&nbsp;Shaoxuan Wei ,&nbsp;Haoqi Zou ,&nbsp;Jingjing Liu ,&nbsp;Shouling Wu ,&nbsp;Faming Tian","doi":"10.1016/j.bone.2025.117645","DOIUrl":"10.1016/j.bone.2025.117645","url":null,"abstract":"<div><div>We aimed to evaluate the effect of a combination of the cumulative remnant cholesterol (cumRC) concentration and the cumulative monocyte/lymphocyte ratio (cumMLR) or the cumulative systemic inflammation response index (cumSIRI) on the risk of fragility fracture. We studied 38,900 participants who completed the Kailuan health examinations in 2006, 2008, and 2010. The baseline characteristics of six groups created according to the cumRC tertile and cumMLR median were compared. The incidence density was calculated, and the log-rank test was employed to compare the cumulative incidences. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95 % confidence intervals (CIs), and the restricted cubic spline method was used to evaluate the possibility of non-linear relationships of cumRC, cumMLR, or cumSIRI with the risk of fragility fracture. Additional analyses were performed after stratification according to body mass index (BMI ≥ or &lt;24 kg/m²). During a median follow-up period of 12.00 years, a total of 581 fragility fractures occurred. Compared to the medium cumRC &amp; low cumMLR group, the risk of fragility fracture was highest in the high cumRC &amp; high cumMLR group (HR = 1.69, 95 % CI: 1.24–2.30), followed by the low cumRC &amp; high cumMLR group (HR = 1.59, 95 % CI: 1.17–2.15). Compared to the medium cumRC &amp; low cumSIRI, the risk of fragility fracture was highest in the low cumRC &amp; high cumSIRI group (HR = 1.62, 95 % CI: 1.18–2.22), followed by the high cumRC &amp; high cumSIRI group (HR = 1.59, 95 % CI: 1.16–2.19). Thus, the combination of either excessively low or high cumRC and high cumMLR or cumSIRI is associated with a higher risk of fragility fracture, and this association is particularly marked for individuals with BMI &lt;24 kg/m².</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117645"},"PeriodicalIF":3.6,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical evidence linking osteoporosis and the gut microbiome in postmenopausal females: A systematic review","authors":"Kyungjae Lee ,&nbsp;Hojun Kim ,&nbsp;Jing-Hua Wang","doi":"10.1016/j.bone.2025.117644","DOIUrl":"10.1016/j.bone.2025.117644","url":null,"abstract":"<div><h3>Background</h3><div>Recent studies have highlighted the intricate relationship between gut microbiome (GM) and osteoporosis (OP), particularly in postmenopausal females. However, the precise mechanisms underlying this association remain unclear.</div></div><div><h3>Materials and methods</h3><div>This retrospective review and meta-analysis aimed to elucidate the role of GM in postmenopausal OP (PMO) by synthesizing clinical findings from recent literature. A systematic search of four databases (PubMed, Google Scholar, Cochrane Library, and Web of Science) identified 16 relevant clinical studies published between January 2000 and July 2025.</div></div><div><h3>Results</h3><div>A total of 1520 postmenopausal females (mean age: 59.25 ± 6.63 years) were included, comprising 656 patients with PMO and 864 healthy controls (HC). A meta-analysis of gut microbial α diversity revealed a significant reduction (<em>p</em> = 0.04) in the abundance-based coverage estimator (ACE) index in patients with PMO, indicating a loss of microbial richness. At the same time, β-diversity findings were inconsistent across studies. Taxonomic analysis confirmed differences between patients and HC at the phylum and genus levels. PMO is characterized by a significant increase in primary bile acids and a reduction in tryptophan and daidzein metabolism at the metabolic level. Additionally, Patients with PMO exhibited markedly lower serum estradiol levels, higher levels of lipopolysaccharide and tumor necrosis factor-α, a higher proportion of Th17 cells, and a lower Treg cell population, indicating a pro-inflammatory state.</div></div><div><h3>Conclusion</h3><div>Overall, this review provides a comprehensive synthesis of current clinical evidence on the role of GM in PMO, emphasizing its potential impact on bone metabolism. Given these findings, targeting the composition of gut microbiota and its metabolites may offer a promising therapeutic strategy for mitigating OP in postmenopausal females.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117644"},"PeriodicalIF":3.6,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone loss and impaired formation are associated with shared vascular changes in type 1 and type 2 diabetic mice with systemic microangiopathy","authors":"Solène Viallon ,&nbsp;Dalia Ibarissen ,&nbsp;Elodie Fauritte ,&nbsp;Clémentine Robert-Lagier ,&nbsp;Zhiguo He ,&nbsp;Bernard Roche ,&nbsp;Marie-Hélène Lafage-Proust","doi":"10.1016/j.bone.2025.117642","DOIUrl":"10.1016/j.bone.2025.117642","url":null,"abstract":"<div><div>Diabetes increases fracture risk, due to multifactorial bone fragility. Since bone vascularization is essential for bone health, we hypothesized that vascular alterations contribute to diabetic bone disease. We used two models of type 1 (T1D) and 2 (T2D) diabetes in C57Bl/6 male mice. For T1D, 8-week-old mice received saline (CTR1, n = 25) or streptozotocin (STZ, 185 mg/kg, n = 28). For T2D, 4-week-old mice were fed standard (CTR2, n = 23) or a high-fat (n = 24) diet, followed by STZ (60 and 40 mg/kg). Tibia bone parameters were assessed longitudinally at baseline, 6 (M6; both types) or 12 months (M12; T2D) by μCT. Bone perfusion, marrow flow cytometry, quantitative femoral histomorphometry and vascular immunohistochemistry of Endomucin⁺-endothelial cells and Leptin-Receptor⁺ pericytes, which include osteoblast progenitors, were performed. Retina and kidney microangiopathy were evaluated. By M6, T1D mice were hyperglycemic, lost 25 % of trabecular and cortical bone with markedly suppressed bone formation and a 30 % decreased bone perfusion, while exhibiting retinopathy. At M6, T2D mice were obese and hyperglycemic, with unchanged trabecular bone mass and osteoblastic formation but lower cortical mass, compared to CTR2. By M12, T2D displayed retinopathy together with trabecular and cortical bone loss, reduced perfusion and bone formation, while Endomucin⁺ marrow vessel density increased. In both models, vascular coverage by LepR⁺-pericytes increased at all time points. Overall, STZ-related T1D induced early and severe bone vascular dysfunction associated with systemic microangiopathy. In T2D, similar changes developed later. Diabetic bone fragility may involve altered microvascular remodeling and impaired pericyte mobilization.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117642"},"PeriodicalIF":3.6,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone microarchitecture and strength in men with prostate cancer with and without prevalent vertebral fractures at the initiation of androgen deprivation therapy","authors":"Marsha M. van Oostwaard ,&nbsp;Melissa S.A.M. Bevers ,&nbsp;Johanna H.M. Driessen ,&nbsp;Marc de Jong ,&nbsp;Maryska L.G. Janssen Heijnen ,&nbsp;Caroline E. Wyers ,&nbsp;Joop P. van den Bergh","doi":"10.1016/j.bone.2025.117643","DOIUrl":"10.1016/j.bone.2025.117643","url":null,"abstract":"<div><div>Androgen deprivation therapy (ADT) in prostate cancer (PCa) is associated with an increased fracture risk. However, studies on the prevalence of low areal bone mineral density (aBMD) and vertebral fractures (VFs) at the initiation of ADT and data on bone microarchitecture and strength are scarce. The aims of this study were 1) to evaluate bone microarchitecture and strength in men with PCa at the initiation of ADT in a real-world cohort as compared to normative data, and 2) to investigate whether the presence of VF at the initiation of ADT is associated with bone microarchitecture and strength.</div><div>The cohort consisted of men with PCa who were referred to our PCa care pathway for fracture prevention at ADT initiation, between January 2019 and October 2023. All men underwent dual-energy X-ray absorptiometry (DXA), X-ray of the spine, and high-resolution peripheral quantitative CT (HR-pQCT) at ADT initiation. VFs were identified morphometrically on X-ray using Genant's VF classification. Men with bone metastases, previous ADT treatment, &gt;1 administration of ADT prior to entering the pathway, or prior or current use of anti-osteoporosis medication were excluded from the study. HR-pQCT parameters were compared with normative data to calculate <em>Z</em>-scores. Linear regression analyses were performed (covariates: age, body mass index, previous fractures, prostate-specific antigen level, time since diagnosis, chronic obstructive pulmonary disease, and rheumatoid arthritis) to study the relationship between VFs and bone microarchitecture.</div><div>A total of 256 men (median age: 73.9, IQR: 69.5–78.1 yrs) were evaluated, of whom 10 (3.9 %) had osteoporosis and 85 (33.2 %) at least one prevalent VF. Of the 85 men with ≥1 VF, 46 had 1 VF (54.1 %) and the other 39 (45.9 %) had at least 2 VFs. A total of 473 HR-pQCT scans of sufficient quality were analysed (<em>n</em> = 233 radius, <em>n</em> = 240 tibia). The mean <em>Z</em>-scores were ≥ −1 for all HR-pQCT parameters at both the radius and tibia in the entire cohort as well as when stratified by VF. Linear regression analyses showed that the presence of ≥1VF was associated with a larger trabecular and smaller cortical area, lower total and trabecular BMD, and lower trabecular and cortical thickness of the tibia. There were no significant associations between the HR-pQCT parameters at the distal radius or with femoral neck aBMD.</div><div>In conclusion, men with PCa had a bone microarchitecture and strength comparable to normative data at the time of ADT initiation. However, men with at least one prevalent VF had impaired microarchitecture at the tibia compared to those without prevalent VFs.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117643"},"PeriodicalIF":3.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing Wnt signaling lowers fracture incidence in a severe mouse model of Osteogenesis Imperfecta","authors":"Giulia Montagna ,&nbsp;Stephanie Lee ,&nbsp;Austin Baacke ,&nbsp;Matthew L. Warman ,&nbsp;Christina M. Jacobsen","doi":"10.1016/j.bone.2025.117641","DOIUrl":"10.1016/j.bone.2025.117641","url":null,"abstract":"<div><div>Increased fracture is a hallmark feature of the skeletal disorder Osteogenesis Imperfecta (OI). A neutralizing antibody against sclerostin, an endogenous Wnt signaling inhibitor, has been FDA-approved for osteoporosis and is now in clinical trials for OI. This anti-sclerostin antibody increased bone mass and skeletal strength in several preclinical models of OI.</div><div>Because <em>in vivo</em> fracture incidence is the primary outcome measure in human OI clinical trials, we examined the effect of enhancing Wnt signaling in a preclinical mouse model of severe, autosomal dominant OI (the <em>Col1a1^Aga2/+</em> mouse). We genetically enhanced Wnt signaling using the <em>Lrp5^A214V</em> allele, which makes the Wnt co-receptor LRP5 resistant to sclerostin inhibition. By crossing <em>Col1a1^Aga2/+</em> sires with <em>Lrp5^A214V/+</em> dams, we generated pups with OI alone and pups with OI plus enhanced Wnt signaling. We radiographically examined these animals for fractures at 5, 9, and 13 weeks of age and also measured their mobility using a Holeboard assay.</div><div>We found that enhanced Wnt signaling significantly reduced fracture numbers in this OI model by 30 % at each age but did not significantly affect mobility. These data indicate that an enhanced Wnt signaling decreases fracture incidence in a preclinical model of severe OI and suggest that lower fracture rates could be achieved by administering anti-sclerostin antibodies to OI patients.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"202 ","pages":"Article 117641"},"PeriodicalIF":3.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating single-cell and bulk transcriptome analysis of fibroblast growth factor 23 (FGF23)-producing mesenchymal tumors reveals molecular basis of its secretory phenotype","authors":"Sofia A. Gronskaia ,&nbsp;Ruslan M. Deviatiiarov ,&nbsp;Vladimir P. Chekhonin ,&nbsp;Ivan I. Dedov ,&nbsp;Yuriy V. Buklemishev ,&nbsp;Irena V. Boulytcheva ,&nbsp;Marina V. Utkina ,&nbsp;Sergei V. Popov ,&nbsp;Svetlana S. Rodionova ,&nbsp;Liudmila Y. Rozhinskaya ,&nbsp;Oleg A. Gusev ,&nbsp;Zhanna E. Belaya","doi":"10.1016/j.bone.2025.117640","DOIUrl":"10.1016/j.bone.2025.117640","url":null,"abstract":"<div><div>Tumor-induced osteomalacia (TIO) is a rare disorder caused by a phosphaturic mesenchymal tumor (PMT) secreting fibroblast growth factor 23 (FGF23).</div><div>The aim of this study was to analyze PMTs for their transcriptomic characteristics. We performed single-cell RNA (<em>n</em> = 3) alongside bulk RNA sequencing of PMTs (<em>n</em> = 5) and surrounding bone tissue (<em>n</em> = 4) obtained during tumor removal in 10 patients (age 44 (41;64), serum phosphate (Pi)- 0.54 (0.43; 0.59) mM/L, FGF23–113 (40; 205) pg/ml). We revealed a total of 22,449 cells divided into 13 different categories. We identified the heterogeneity of the PMT cell cluster and subsequently divided it into two tumor clusters 1 and 2 characterized by the deeper epithelial-mesenchymal phenotype transition, higher <em>FGF23</em> expression as well as various SNP and CNV. We further identified tumor cell differentiation driving regulons <em>ERG</em> and <em>EGR3</em>, based on scoring by allele expression and velocity based pseudotime on a trajectory that may play a critical role in the tumorigenesis of PMTs. In both single-cell and bulk transcriptome analysis we found upregulation of vesicle-specific and exocytosis associated genes (<em>SLC30A3, SYT1, STX1A</em> and <em>SNAP25</em>) which most likely represent molecular mechanisms of active secretion in all PMT samples. We report transmembrane protein coding genes expressed in all PMTs specifically in tumor cell clusters <em>(PHEX, ERBB4, PCDH7, LRRFIP2)</em> which are suggested as potential diagnostic targets. We confirmed the presence of <em>FN1-FGFR1</em> fusion genes and <em>Klotho</em> expression in most PMTs (6 out of 8).</div><div>Conclusion: specific SNARE proteins gene upregulation along with transcriptional signatures of PMT offer new insights into its pathogenesis which may be further studied for diagnostic and therapeutic interventions.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117640"},"PeriodicalIF":3.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Childhood obesity influences mid-to-late life bone health through shared genetic architecture","authors":"Maoyao Xia ,&nbsp;Yang Qu ,&nbsp;Bowen Lei ,&nbsp;Yangdan Zhong ,&nbsp;Tao Han ,&nbsp;Linna Sha ,&nbsp;Jiangbo Zhu ,&nbsp;Xin Song ,&nbsp;Bin Yang ,&nbsp;Qin Deng ,&nbsp;Jiaojiao Hou ,&nbsp;Sirui Zheng ,&nbsp;Rong Xiang ,&nbsp;Xunying Zhao ,&nbsp;Ting Yu ,&nbsp;Jinyu Zhou ,&nbsp;Mengyu Fan ,&nbsp;Xia Jiang","doi":"10.1016/j.bone.2025.117639","DOIUrl":"10.1016/j.bone.2025.117639","url":null,"abstract":"<div><h3>Background</h3><div>Despite higher body mass index (BMI) in adulthood being widely acknowledged as protective for bone mineral density (BMD), the effect of childhood BMI on adult BMD remains inconclusive. This study aims to elucidate the shared genetic basis underlying childhood BMI and adult heel estimated BMD (eBMD).</div></div><div><h3>Methods</h3><div>We conducted a comprehensive genome-wide cross-trait analysis to determine the genetic correlations, pleiotropic loci, and causal relationships between childhood BMI and adult eBMD. Summary statistics were collected from the hitherto largest available genome-wide association studies conducted for childhood BMI (<em>N</em> = 62,026) and adult eBMD (<em>N</em> = 426,824) of European individuals.</div></div><div><h3>Results</h3><div>A significant positive overall genetic correlation was observed for childhood BMI and adult eBMD (<span><math><msub><mi>r</mi><mi>g</mi></msub></math></span> = 0.09, <em>P</em> = 4.00 × 10⁻⁴), which was supported by the significant local signal observed in one genomic region (5q21.3). The shared genetic basis was further emphasized by 55 pleiotropic loci identified through the cross-trait meta-analysis, 11 shared gene-tissue pairs observed in transcriptome-wide association study, and a robust causal relationship demonstrated by Mendelian randomization (<span><math><mi>β</mi></math></span> = 0.12, 95 %CIs = 0.06–0.18).</div></div><div><h3>Conclusions</h3><div>Our work highlights the substantial shared genetic influence and putative causal link underlying childhood BMI and mid-to-late life eBMD, offering new avenues for personalized prevention strategies against osteoporosis.</div></div><div><h3>Trial registration</h3><div>Not applicable.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"201 ","pages":"Article 117639"},"PeriodicalIF":3.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145042402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}