Pub Date : 2025-07-26DOI: 10.1016/j.jbo.2025.100705
Zhizhong Liang , Yuxia Shi , Mao Wang , Liqiang Zhang
Background
Regulators of G-protein signaling 1 (RGS1) has been reported to be involved in immune cell regulation in many cancer types. However, the specific role and mechanism in osteosarcoma (OS) progression and macrophage activation remain unclear.
Methods
Levels of mRNA and protein were examined using qRT-PCR and western blotting. Transwell assay, wound healing assay, EdU assay and flow cytometry were used to investigate OS cell invasion, migration, proliferation and apoptosis. Xenografts in mice were established for in vivo assay. Macrophage M2 polarization was evaluated by detecting CD206 + macrophages by flow cytometry. ELISA analysis detected IL-6 and TGF-β1 levels. Methylated RNA immunoprecipitation assay was applied to explore the specific binding of RGS1 and METTL3 (methyltransferase-like 3).
Results
RGS1 was highly expressed in OS tissues and cells. The silencing of RGS1 suppressed OS cell invasion, migration, growth and impaired immune response by inhibiting macrophage M2 polarization and M2 macrophage-mediated release of IL-10 and TGF-β1. Mechanistically, METTL3 promoted RGS1 m6A modification and stabilized its expression. METTL3 deficiency also inhibited OS cell invasion, migration, growth and macrophage M2 polarization, while these effects could be abolished by RGS1 overexpression. Besides that, IL–10 elevation induced by M2 macrophages promoted OS cell oncogenic phenotypes.
Conclusion
METTL3 stabilized RGS1 mRNA in an m6A-dependent manner to promote the tumorigenicity and macrophage M2 polarization in osteosarcoma, suggesting a novel insight into the therapy of osteosarcoma.
{"title":"RGS1 stabilized by METTL3-mediated m6A modification promotes the tumorigenicity and macrophage M2 polarization in osteosarcoma","authors":"Zhizhong Liang , Yuxia Shi , Mao Wang , Liqiang Zhang","doi":"10.1016/j.jbo.2025.100705","DOIUrl":"10.1016/j.jbo.2025.100705","url":null,"abstract":"<div><h3>Background</h3><div>Regulators of G-protein signaling 1 (RGS1) has been reported to be involved in immune cell regulation in many cancer types. However, the specific role and mechanism in osteosarcoma (OS) progression and macrophage activation remain unclear.</div></div><div><h3>Methods</h3><div>Levels of mRNA and protein were examined using qRT-PCR and western blotting. Transwell assay, wound healing assay, EdU assay and flow cytometry were used to investigate OS cell invasion, migration, proliferation and apoptosis. Xenografts in mice were established for in vivo assay. Macrophage M2 polarization was evaluated by detecting CD206 + macrophages by flow cytometry. ELISA analysis detected IL-6 and TGF-β1 levels. Methylated RNA immunoprecipitation assay was applied to explore the specific binding of RGS1 and METTL3 (methyltransferase-like 3).</div></div><div><h3>Results</h3><div>RGS1 was highly expressed in OS tissues and cells. The silencing of RGS1 suppressed OS cell invasion, migration, growth and impaired immune response by inhibiting macrophage M2 polarization and M2 macrophage-mediated release of IL-10 and TGF-β1. Mechanistically, METTL3 promoted RGS1 m6A modification and stabilized its expression. METTL3 deficiency also inhibited OS cell invasion, migration, growth and macrophage M2 polarization, while these effects could be abolished by RGS1 overexpression. Besides that, IL–10 elevation induced by M2 macrophages promoted OS cell oncogenic phenotypes.</div></div><div><h3>Conclusion</h3><div>METTL3 stabilized RGS1 mRNA in an m6A-dependent manner to promote the tumorigenicity and macrophage M2 polarization in osteosarcoma, suggesting a novel insight into the therapy of osteosarcoma.</div></div>","PeriodicalId":48806,"journal":{"name":"Journal of Bone Oncology","volume":"54 ","pages":"Article 100705"},"PeriodicalIF":3.5,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144781766","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}
Pub Date : 2025-07-22DOI: 10.1016/j.jbo.2025.100704
Claudia Alcira Espinoza-González , Citlalli Oyuki Mendoza-Chacón , Pierrick G.J. Fournier , Gabriela Velasco-Loyden , Felipe Olvera , Victoria Chagoya de Sánchez , Rafael Vazquez-Duhalt , Patricia Juárez
Triple-negative breast cancer (TNBC) is an aggressive subtype of cancer characterized by limited therapeutic options and a propensity to form metastasis, particularly to bone. Given the mortality and morbidity linked to TNBC, the advancement of novel and effective therapies is essential. This work studies the potential of an adenosine derivative compound (IFC-305) as a therapeutic agent for breast cancer bone metastasis. It focuses on its effects on bone metastasis, including cell viability, migration, cell cycle, and apoptosis in vitro. In vitro assays demonstrated that IFC-305 significantly reduced TNBC cell viability and migration in a dose-dependent manner. Additionally, it promoted cell cycle arrest and decreased the proportion of cells in the S phase, although it did not induce apoptosis in 4T1 cells. Furthermore, in vivo experiments using a murine model of bone metastasis revealed that treatment with IFC-305 attenuated osteolytic lesions associated with breast cancer metastasis. Importantly, our findings highlight an interaction between this adenosine derivative and the TGF-β signaling pathway. The derivative compound effectively inhibited SMAD2/3 phosphorylation, a key mediator of TGF-β signaling pathway involved in cell growth, differentiation, migration and metastatic progression. Besides, IFC-305 reduced TGF-β regulated PMPEA1 expression, a gene associated with cancer stemness and tumor invasion. These findings provide evidence for the therapeutic potential of the IFC-305 in treating metastatic breast cancer in the bone and warrant further investigation to fully elucidate its mechanism of action and evaluate its clinical translatability.
{"title":"IFC-305, an adenosine derivative, inhibits the osteolytic metastases of triple-negative breast cancer","authors":"Claudia Alcira Espinoza-González , Citlalli Oyuki Mendoza-Chacón , Pierrick G.J. Fournier , Gabriela Velasco-Loyden , Felipe Olvera , Victoria Chagoya de Sánchez , Rafael Vazquez-Duhalt , Patricia Juárez","doi":"10.1016/j.jbo.2025.100704","DOIUrl":"10.1016/j.jbo.2025.100704","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is an aggressive subtype of cancer characterized by limited therapeutic options and a propensity to form metastasis, particularly to bone. Given the mortality and morbidity linked to TNBC, the advancement of novel and effective therapies is essential. This work studies the potential of an adenosine derivative compound (IFC-305) as a therapeutic agent for breast cancer bone metastasis. It focuses on its effects on bone metastasis, including cell viability, migration, cell cycle, and apoptosis <em>in vitro</em>. <em>In vitro</em> assays demonstrated that IFC-305 significantly reduced TNBC cell viability and migration in a dose-dependent manner. Additionally, it promoted cell cycle arrest and decreased the proportion of cells in the S phase, although it did not induce apoptosis in 4T1 cells. Furthermore, <em>in vivo</em> experiments using a murine model of bone metastasis revealed that treatment with IFC-305 attenuated osteolytic lesions associated with breast cancer metastasis. Importantly, our findings highlight an interaction between this adenosine derivative and the TGF-β signaling pathway. The derivative compound effectively inhibited SMAD2/3 phosphorylation, a key mediator of TGF-β signaling pathway involved in cell growth, differentiation, migration and metastatic progression. Besides, IFC-305 reduced TGF-β regulated PMPEA1 expression, a gene associated with cancer stemness and tumor invasion. These findings provide evidence for the therapeutic potential of the IFC-305 in treating metastatic breast cancer in the bone and warrant further investigation to fully elucidate its mechanism of action and evaluate its clinical translatability.</div></div>","PeriodicalId":48806,"journal":{"name":"Journal of Bone Oncology","volume":"54 ","pages":"Article 100704"},"PeriodicalIF":3.5,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723375","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}
Evidence regarding the effectiveness of rehabilitation treatments in patients with bone metastases remains limited. This study evaluated the implementation and effectiveness of rehabilitation in patients with bone metastases who did not undergo surgery. This retrospective study included 200 patients with nonsurgically treated bone metastases at our institution. The patients were categorized into a rehabilitation group (R group, n = 61) and a non-rehabilitation group (N group, n = 139). Over the course of one month, we compared activities of daily living (ADL), assessed using the Barthel Index (BI), quality of life (QOL), measured using the EuroQoL-5 Dimension (EQ-5D), and demographic and clinical characteristics. Propensity score matching was conducted to minimize selection bias. After matching, 31 patients in each group were included in the analysis. No statistically significant differences were observed in baseline BI and EQ-5D scores between the two groups. In the R group, BI improved significantly from 80 (interquartile range [IQR]: 60–100) to 90 (IQR: 70–100), and EQ-5D improved from 0.444 (IQR: 0.282–0.608) to 0.608 (IQR: 0.533–0.768). In contrast, no improvements were observed in either score in the N group. Chemotherapy was identified as a significant factor associated with improvements in BI (odds ratio 4.03) and EQ-5D (odds ratio 5.29). Rehabilitation may be a valuable treatment option for nonsurgically treated patients with bone metastases, warranting further validation in prospective studies.
{"title":"Effectiveness of rehabilitation treatment for bone metastasis patients without surgical intervention: A propensity score matching analysis","authors":"Ryo Yoshikawa , Yasumitsu Fujii , Ryoga Kashima , Wataru Saho , Risa Harada , Daisuke Makiura , Katsuya Fujiwara , Junichiro Inoue , Yoshiki Takeoka , Ryoko Sawada , Naomasa Fukase , Keisuke Oe , Hitomi Hara , Kenichiro Kakutani , Toshihiro Akisue , Yoshitada Sakai","doi":"10.1016/j.jbo.2025.100703","DOIUrl":"10.1016/j.jbo.2025.100703","url":null,"abstract":"<div><div>Evidence regarding the effectiveness of rehabilitation treatments in patients with bone metastases remains limited. This study evaluated the implementation and effectiveness of rehabilitation in patients with bone metastases who did not undergo surgery. This retrospective study included 200 patients with nonsurgically treated bone metastases at our institution. The patients were categorized into a rehabilitation group (R group, n = 61) and a non-rehabilitation group (N group, n = 139). Over the course of one month, we compared activities of daily living (ADL), assessed using the Barthel Index (BI), quality of life (QOL), measured using the EuroQoL-5 Dimension (EQ-5D), and demographic and clinical characteristics. Propensity score matching was conducted to minimize selection bias. After matching, 31 patients in each group were included in the analysis. No statistically significant differences were observed in baseline BI and EQ-5D scores between the two groups. In the R group, BI improved significantly from 80 (interquartile range [IQR]: 60–100) to 90 (IQR: 70–100), and EQ-5D improved from 0.444 (IQR: 0.282–0.608) to 0.608 (IQR: 0.533–0.768). In contrast, no improvements were observed in either score in the N group. Chemotherapy was identified as a significant factor associated with improvements in BI (odds ratio 4.03) and EQ-5D (odds ratio 5.29). Rehabilitation may be a valuable treatment option for nonsurgically treated patients with bone metastases, warranting further validation in prospective studies.</div></div>","PeriodicalId":48806,"journal":{"name":"Journal of Bone Oncology","volume":"53 ","pages":"Article 100703"},"PeriodicalIF":3.4,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678759","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}
Pub Date : 2025-07-12DOI: 10.1016/j.jbo.2025.100702
Yunpeng Cui , Xuedong Shi , Qiwei Wang , Wence Wu , Yuanxing Pan , Bing Wang , Mingxing Lei
Purpose
Coatomer protein complex subunit beta 2 (COPB2) is a crucial component of the coatomer protein complex I, responsible for vesicle transport. Previous studies have indicated that COPB2 is highly expressed in malignant tumors and is involved in cell proliferation and apoptosis. However, the role of COPB2 in osteosarcoma and its underlying mechanisms remain unclear. This study aimed to investigate the impact of COPB2 on proliferation, apoptosis, and colony formation in human osteosarcoma cells, as well as to explore potential mechanisms.
Methods
Kaplan-Meier survival analysis was conducted to assess the association between COPB2 expression and the prognosis of osteosarcoma patients using data extracted from the Cancer Genome Atlas (TCGA) database. Additionally, COPB2 expression was examined in osteosarcoma tissue samples and four osteosarcoma cell lines using immunohistochemistry and quantitative real-time PCR (qRT-PCR). COPB2 expression was downregulated using siRNA in U2OS and SAOS-2 human osteosarcoma cells. Cell proliferation and colony formation were assessed using Cellomics/Celigo and Giemsa staining, respectively. Flow cytometry was used to evaluate cell cycle distribution and apoptosis. Tumor growth was evaluated in vivo model. Furthermore, the regulation mechanism of COPB2 on osteosarcoma cells was investigated using the Human Phospho-Kinase Array Kit.
Results
Patients with high COPB2 expression exhibited shorter overall survival and disease-free survival compared to those with low COPB2 expression. COPB2 was found to be highly expressed in osteosarcoma tissue samples and cell lines. Silencing of COPB2 significantly inhibited cell proliferation and colony formation. Additionally, COPB2 silencing altered the cell cycle distribution, leading to cell cycle arrest in the G2 phase, and promoted cell apoptosis in osteosarcoma cells. Further investigations revealed that COPB2 silencing inhibited tumor growth and lung metastases of osteosarcoma cells in vivo, and its effects on cell proliferation and apoptosis may be mediated through the regulation of kinase phosphorylation levels.
Conclusions
COPB2 expression is increased in osteosarcoma cells and plays a crucial role in cell growth regulation. Silencing of COPB2 inhibits cell proliferation, colony formation, and promotes cell apoptosis. Furthermore, COPB2 silencing inhibits tumor growth in vivo, suggesting its potential as an important therapeutic target in treating osteosarcoma.
cocoatomer protein complex subunit beta 2 （COPB2）是cocoatomer protein complex I的重要组成部分，负责囊泡运输。既往研究表明，COPB2在恶性肿瘤中高表达，参与细胞增殖和凋亡。然而，COPB2在骨肉瘤中的作用及其潜在机制尚不清楚。本研究旨在探讨COPB2对人骨肉瘤细胞增殖、凋亡和集落形成的影响，并探讨其可能的机制。方法利用癌症基因组图谱（TCGA）数据库的数据进行kaplan - meier生存分析，评估COPB2表达与骨肉瘤患者预后的关系。此外，利用免疫组织化学和定量实时PCR （qRT-PCR）检测COPB2在骨肉瘤组织样本和四种骨肉瘤细胞系中的表达。在U2OS和SAOS-2人骨肉瘤细胞中，利用siRNA下调COPB2的表达。细胞组学/Celigo和Giemsa染色分别评估细胞增殖和集落形成。流式细胞术检测细胞周期分布及凋亡情况。在体内模型中评估肿瘤生长情况。此外，利用Human Phospho-Kinase Array Kit研究COPB2对骨肉瘤细胞的调控机制。结果COPB2高表达患者的总生存期和无病生存期均短于COPB2低表达患者。发现COPB2在骨肉瘤组织样本和细胞系中高度表达。沉默COPB2可显著抑制细胞增殖和集落形成。此外，COPB2沉默改变了细胞周期分布，导致细胞周期阻滞在G2期，促进骨肉瘤细胞凋亡。进一步研究发现，COPB2沉默在体内抑制骨肉瘤细胞的肿瘤生长和肺转移，其对细胞增殖和凋亡的影响可能是通过调节激酶磷酸化水平介导的。结论scopb2在骨肉瘤细胞中表达升高，在骨肉瘤细胞生长调控中起重要作用。沉默COPB2可抑制细胞增殖、集落形成并促进细胞凋亡。此外，COPB2沉默在体内抑制肿瘤生长，这表明它有可能成为治疗骨肉瘤的重要治疗靶点。
{"title":"COPB2 as a key regulator of cell growth in human osteosarcoma cells: Potential therapeutic target and prognostic indicator","authors":"Yunpeng Cui , Xuedong Shi , Qiwei Wang , Wence Wu , Yuanxing Pan , Bing Wang , Mingxing Lei","doi":"10.1016/j.jbo.2025.100702","DOIUrl":"10.1016/j.jbo.2025.100702","url":null,"abstract":"<div><h3>Purpose</h3><div>Coatomer protein complex subunit beta 2 (COPB2) is a crucial component of the coatomer protein complex I, responsible for vesicle transport. Previous studies have indicated that COPB2 is highly expressed in malignant tumors and is involved in cell proliferation and apoptosis. However, the role of COPB2 in osteosarcoma and its underlying mechanisms remain unclear. This study aimed to investigate the impact of COPB2 on proliferation, apoptosis, and colony formation in human osteosarcoma cells, as well as to explore potential mechanisms.</div></div><div><h3>Methods</h3><div>Kaplan-Meier survival analysis was conducted to assess the association between COPB2 expression and the prognosis of osteosarcoma patients using data extracted from the Cancer Genome Atlas (TCGA) database. Additionally, COPB2 expression was examined in osteosarcoma tissue samples and four osteosarcoma cell lines using immunohistochemistry and quantitative real-time PCR (qRT-PCR). COPB2 expression was downregulated using siRNA in U2OS and SAOS-2 human osteosarcoma cells. Cell proliferation and colony formation were assessed using Cellomics/Celigo and Giemsa staining, respectively. Flow cytometry was used to evaluate cell cycle distribution and apoptosis. Tumor growth was evaluated in vivo model. Furthermore, the regulation mechanism of COPB2 on osteosarcoma cells was investigated using the Human Phospho-Kinase Array Kit.</div></div><div><h3>Results</h3><div>Patients with high COPB2 expression exhibited shorter overall survival and disease-free survival compared to those with low COPB2 expression. COPB2 was found to be highly expressed in osteosarcoma tissue samples and cell lines. Silencing of COPB2 significantly inhibited cell proliferation and colony formation. Additionally, COPB2 silencing altered the cell cycle distribution, leading to cell cycle arrest in the G2 phase, and promoted cell apoptosis in osteosarcoma cells. Further investigations revealed that COPB2 silencing inhibited tumor growth and lung metastases of osteosarcoma cells in vivo, and its effects on cell proliferation and apoptosis may be mediated through the regulation of kinase phosphorylation levels.</div></div><div><h3>Conclusions</h3><div>COPB2 expression is increased in osteosarcoma cells and plays a crucial role in cell growth regulation. Silencing of COPB2 inhibits cell proliferation, colony formation, and promotes cell apoptosis. Furthermore, COPB2 silencing inhibits tumor growth in vivo, suggesting its potential as an important therapeutic target in treating osteosarcoma.</div></div>","PeriodicalId":48806,"journal":{"name":"Journal of Bone Oncology","volume":"53 ","pages":"Article 100702"},"PeriodicalIF":3.4,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144653531","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}
Pub Date : 2025-07-12DOI: 10.1016/j.jbo.2025.100701
Fan Yang, Mao Wang
Background
N-acetyltransferase 10 (NAT10) acts as the “writer” of N4-acetylcytidine (ac4C) modification in tumor progression, including osteosarcoma (OS). Its molecular mechanism in OS remains not fully clear. This study endeavored to disclose the upstream and downstream mechanism of NAT10 related to Yin Yang 1 protein (YY1) and integrin β3 (ITGB3) in OS.
Methods
Gene mRNA and protein levels were assayed via real-time quantitative PCR and Western blotting. Cell counting kit-8, EdU assay, flow cytometry/TUNEL staining assay, transwell assay, and scratch assay were conducted to assess cell viability, proliferation, apoptosis, invasion, and migration. Interaction analysis was completed through ac4C RNA immunoprecipitation (ac4c RIP), RIP, chromatin IP and dual-luciferase reporter assay. In vivo assay was carried out using xenograft models in mice.
Results
OS tissues and cells showed the high expression of NAT10. Cell proliferation, invasion, and migration were suppressed but apoptosis was enhanced in NAT10-silenced OS cells. GSE237541 dataset has predicted the inhibition of ITGB3 after NAT10 knockdown, and PACES website predicted ac4C site in ITGB3. Furthermore, it was found that NAT10 could up-regulate ITGB3 expression by mediating ac4C acetylation. ITGB3 overexpression recused OS cell progression inhibition caused by NAT10 knockdown. Jaspar predicted the binding between YY1 and NAT10 promoter. YY1 could activate the transcriptional regulation of NAT10 to increase NAT10 expression, and YY1 depletion blocked cell malignant behaviors via reducing NAT10 expression. More importantly, YY1 interacted with NAT10 to up-regulate ITGB3 expression. In vivo, NAT10/ITGB3 axis also promoted OS tumor growth in mice.
Conclusion
YY1 was firstly affirmed to regulate transcription of NAT10, and NAT10 was firstly indicated to mediate ac4C modification of ITGB3. YY1-activated NAT10 could affect ITGB3 and then modulated the malignant development of OS.
n -乙酰基转移酶10 （NAT10）在包括骨肉瘤（OS）在内的肿瘤进展中起着n4 -乙酰胞苷（ac4C）修饰的“作者”作用。其在OS中的分子机制尚不完全清楚。本研究旨在揭示在OS中与阴阳1蛋白（YY1）和整合素β3 （ITGB3）相关的NAT10的上下游机制。方法采用实时定量PCR和Western blotting检测各组小鼠基因mRNA和蛋白表达水平。采用细胞计数试剂盒-8、EdU法、流式细胞术/TUNEL染色法、transwell法和划痕法评估细胞活力、增殖、凋亡、侵袭和迁移。通过ac4C RNA免疫沉淀（ac4C RIP）、RIP、染色质IP和双荧光素酶报告基因测定完成相互作用分析。采用小鼠异种移植物模型进行体内实验。结果6个组织和细胞均高表达NAT10。在nat10沉默的OS细胞中，细胞增殖、侵袭和迁移受到抑制，但细胞凋亡增强。GSE237541数据集预测了NAT10敲低后ITGB3的抑制作用，PACES网站预测了ITGB3中的ac4C位点。进一步发现NAT10可以通过介导ac4C乙酰化上调ITGB3的表达。ITGB3过表达可避免NAT10敲低引起的OS细胞进展抑制。Jaspar预测了YY1与NAT10启动子之间的结合。YY1可以激活NAT10的转录调控，增加NAT10的表达，YY1缺失通过降低NAT10的表达来阻断细胞的恶性行为。更重要的是，YY1与NAT10相互作用，上调ITGB3的表达。在体内，NAT10/ITGB3轴也促进了小鼠OS肿瘤的生长。结论yy1首次被证实调控NAT10的转录，NAT10首次被证实介导ITGB3的ac4C修饰。yy1激活的NAT10可影响ITGB3，进而调控OS的恶性发展。
{"title":"Yin Yang 1 protein-activated N-acetyltransferase 10 drives cell malignant progression of osteosarcoma through ac4C acetylation of integrin β3","authors":"Fan Yang, Mao Wang","doi":"10.1016/j.jbo.2025.100701","DOIUrl":"10.1016/j.jbo.2025.100701","url":null,"abstract":"<div><h3>Background</h3><div>N-acetyltransferase 10 (NAT10) acts as the “writer” of N4-acetylcytidine (ac4C) modification in tumor progression, including osteosarcoma (OS). Its molecular mechanism in OS remains not fully clear. This study endeavored to disclose the upstream and downstream mechanism of NAT10 related to Yin Yang 1 protein (YY1) and integrin β3 (ITGB3) in OS.</div></div><div><h3>Methods</h3><div>Gene mRNA and protein levels were assayed via real-time quantitative PCR and Western blotting. Cell counting kit-8, EdU assay, flow cytometry/TUNEL staining assay, transwell assay, and scratch assay were conducted to assess cell viability, proliferation, apoptosis, invasion, and migration. Interaction analysis was completed through ac4C RNA immunoprecipitation (ac4c RIP), RIP, chromatin IP and dual-luciferase reporter assay. <em>In vivo</em> assay was carried out using xenograft models in mice.</div></div><div><h3>Results</h3><div>OS tissues and cells showed the high expression of NAT10. Cell proliferation, invasion, and migration were suppressed but apoptosis was enhanced in NAT10-silenced OS cells. GSE237541 dataset has predicted the inhibition of ITGB3 after NAT10 knockdown, and PACES website predicted ac4C site in ITGB3. Furthermore, it was found that NAT10 could up-regulate ITGB3 expression by mediating ac4C acetylation. ITGB3 overexpression recused OS cell progression inhibition caused by NAT10 knockdown. Jaspar predicted the binding between YY1 and NAT10 promoter. YY1 could activate the transcriptional regulation of NAT10 to increase NAT10 expression, and YY1 depletion blocked cell malignant behaviors via reducing NAT10 expression. More importantly, YY1 interacted with NAT10 to up-regulate ITGB3 expression. <em>In vivo</em>, NAT10/ITGB3 axis also promoted OS tumor growth in mice.</div></div><div><h3>Conclusion</h3><div>YY1 was firstly affirmed to regulate transcription of NAT10, and NAT10 was firstly indicated to mediate ac4C modification of ITGB3. YY1-activated NAT10 could affect ITGB3 and then modulated the malignant development of OS.</div></div>","PeriodicalId":48806,"journal":{"name":"Journal of Bone Oncology","volume":"53 ","pages":"Article 100701"},"PeriodicalIF":3.4,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144653532","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}
Pub Date : 2025-06-23DOI: 10.1016/j.jbo.2025.100700
Wei Chen , Qinglin Jin , Shaohua Du , Shuangwu Dai , Changhe Hou , Zixiong Lei , Lin Zhong , Qingzhu Wei , Haomiao Li
Objective
This study aimed to comprehensively investigate and contrast the imaging manifestations, pathological features, surgical interventions, and prognostic outcomes of Osteofibrous Dysplasia(OFD), Osteofibrous Dysplasia-Like Adamantinoma(OFD-AD), and Adamantinoma(AD). By synthesizing disease profiles and exploring their evolutionary relationships, we sought to identify more effective diagnostic and therapeutic strategies for these conditions.
Methods
A retrospective analysis was conducted on patients diagnosed with OFD, OFD-AD, or AD at our institution between 2015 and 2022. The analysis included a detailed comparison of clinical presentations, imaging findings, and pathological characteristics. We also evaluated the impact of different diagnostic and treatment modalities on patient prognosis and explored potential disease evolution and transformation patterns.
Results
Fifty patients were included in this study: 16 with OFD, 27 with OFD-AD, and 7 with AD. The median age of onset was 14 years for OFD, 6 years for OFD-AD, and 33 years for AD. All diagnoses were confirmed through a combination of clinical evaluation, imaging (X-rays and MRI), and pathological examination. Among the patients, 2 (both with OFD-AD) were managed with observation only. Thirty-seven patients underwent intralesional resection (16 OFD, 20 OFD-AD, and 1 AD), and 11 patients had complete resection (5 OFD-AD and 6 AD). After a minimum follow-up of 24 months (range: 24–––90 months, median: 56 months), 12 patients experienced tumor recurrence (OFD: 2/16, 12.5 %; OFD-AD: 9/25, 36 %; AD: 1/6, 17 %). One patient had concurrent OFD-AD in the fibula and AD in the tibia. In another case, an OFD-AD recurrence 4 years after surgery was later diagnosed as OFD, and an OFD recurrence 2 years after surgery was reclassified as OFD-AD. No distant metastases were observed in any patient.
Conclusion
OFD, OFD-AD, and AD exhibit similarities in clinical and imaging presentations, and their pathological features may represent different stages of a common lesion’s evolution. These diseases have distinct age − related onset patterns and variable recurrence risks. Thus, accurate diagnosis and personalized treatment strategies based on patient characteristics are crucial for effective disease management.
{"title":"Osteofibrous dysplasia, osteofibrous Dysplasia-Like adamantinoma, and adamantinoma: A Single-center retrospective analysis","authors":"Wei Chen , Qinglin Jin , Shaohua Du , Shuangwu Dai , Changhe Hou , Zixiong Lei , Lin Zhong , Qingzhu Wei , Haomiao Li","doi":"10.1016/j.jbo.2025.100700","DOIUrl":"10.1016/j.jbo.2025.100700","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to comprehensively investigate and contrast the imaging manifestations, pathological features, surgical interventions, and prognostic outcomes of <strong>Osteofibrous Dysplasia(OFD)</strong>, <strong>Osteofibrous Dysplasia-Like Adamantinoma(OFD-AD)</strong>, and <strong>Adamantinoma(AD)</strong>. By synthesizing disease profiles and exploring their evolutionary relationships, we sought to identify more effective diagnostic and therapeutic strategies for these conditions.</div></div><div><h3>Methods</h3><div>A retrospective analysis was conducted on patients diagnosed with OFD, OFD-AD, or AD at our institution between 2015 and 2022. The analysis included a detailed comparison of clinical presentations, imaging findings, and pathological characteristics. We also evaluated the impact of different diagnostic and treatment modalities on patient prognosis and explored potential disease evolution and transformation patterns.</div></div><div><h3>Results</h3><div>Fifty patients were included in this study: 16 with OFD, 27 with OFD-AD, and 7 with AD. The median age of onset was 14 years for OFD, 6 years for OFD-AD, and 33 years for AD. All diagnoses were confirmed through a combination of clinical evaluation, imaging (X-rays and MRI), and pathological examination. Among the patients, 2 (both with OFD-AD) were managed with observation only. Thirty-seven patients underwent intralesional resection (16 OFD, 20 OFD-AD, and 1 AD), and 11 patients had complete resection (5 OFD-AD and 6 AD). After a minimum follow-up of 24 months (range: 24–––90 months, median: 56 months), 12 patients experienced tumor recurrence (OFD: 2/16, 12.5 %; OFD-AD: 9/25, 36 %; AD: 1/6, 17 %). One patient had concurrent OFD-AD in the fibula and AD in the tibia. In another case, an OFD-AD recurrence 4 years after surgery was later diagnosed as OFD, and an OFD recurrence 2 years after surgery was reclassified as OFD-AD. No distant metastases were observed in any patient.</div></div><div><h3>Conclusion</h3><div>OFD, OFD-AD, and AD exhibit similarities in clinical and imaging presentations, and their pathological features may represent different stages of a common lesion’s evolution. These diseases have distinct age − related onset patterns and variable recurrence risks. Thus, accurate diagnosis and personalized treatment strategies based on patient characteristics are crucial for effective disease management.</div></div>","PeriodicalId":48806,"journal":{"name":"Journal of Bone Oncology","volume":"53 ","pages":"Article 100700"},"PeriodicalIF":3.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144519166","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}
Pub Date : 2025-06-20DOI: 10.1016/j.jbo.2025.100699
Xuhui Yuan , Jiayu Li , Bo Yu , Feng Cai , Binqi Chen , Jun Liu , Yuanxiang Peng , Duo Zeng , Qi Liao , Lang Liu
Background
Osteosarcoma (OS) remains a highly aggressive malignancy with limited treatment options, necessitating the discovery of novel therapeutic agents. Demethylzeylasteral (DEM), a compound previously shown to exert anti-tumor properties in several malignancies, has not been sufficiently explored for its potential in OS treatment.
Purpose
This study focused on the anti-tumor properties of DEM on OS cells as well as the potential mechanisms.
Methods
OS cell lines (MG63 and 143B) were exposed to varying concentrations of DEM, followed by assessment of diverse cell functions. RNA sequencing was implemented to identify the molecular pathways affected by DEM exposure. The mechanistic underpinnings of DEM’s action were also studied via a series of assays. Additionally, the therapeutic potential was validated utilizing xenograft models.
Results
DEM evidently repressed OS cell proliferation in a dose- and time-dependent fashion, arrested cells in G2/M phase, and facilitated apoptosis through the modulation of the BCL2/BAX ratio. Furthermore, DEM suppressed cell migration and invasion by reversing EMT-related protein expression. RNA sequencing revealed that DEM primarily affected autophagy-related pathways, particularly through the PI3K/AKT signaling. DEM treatment led to an elevation in ROS generation and enhanced autophagic activity, as demonstrated by elevated LC3B puncta formation and autophagy-related protein expression. In vivo, DEM effectively suppressed tumor growth while showing a favorable safety profile.
Conclusion
This study provides comprehensive evidence that DEM exerts potent anti-tumor properties in OS via the PI3K/AKT pathway, highlighting the significance of DEM as a therapeutic candidate for OS.
{"title":"Demethylzeylasteral inhibits proliferation and metastasis of osteosarcoma cells by modulating the PI3K/AKT/Autophagy pathways","authors":"Xuhui Yuan , Jiayu Li , Bo Yu , Feng Cai , Binqi Chen , Jun Liu , Yuanxiang Peng , Duo Zeng , Qi Liao , Lang Liu","doi":"10.1016/j.jbo.2025.100699","DOIUrl":"10.1016/j.jbo.2025.100699","url":null,"abstract":"<div><h3>Background</h3><div>Osteosarcoma (OS) remains a highly aggressive malignancy with limited treatment options, necessitating the discovery of novel therapeutic agents. Demethylzeylasteral (DEM), a compound previously shown to exert anti-tumor properties in several malignancies, has not been sufficiently explored for its potential in OS treatment.</div></div><div><h3>Purpose</h3><div>This study focused on the anti-tumor properties of DEM on OS cells as well as the potential mechanisms.</div></div><div><h3>Methods</h3><div>OS cell lines (MG63 and 143B) were exposed to varying concentrations of DEM, followed by assessment of diverse cell functions. RNA sequencing was implemented to identify the molecular pathways affected by DEM exposure. The mechanistic underpinnings of DEM’s action were also studied via a series of assays. Additionally, the therapeutic potential was validated utilizing xenograft models.</div></div><div><h3>Results</h3><div>DEM evidently repressed OS cell proliferation in a dose- and time-dependent fashion, arrested cells in G2/M phase, and facilitated apoptosis through the modulation of the BCL2/BAX ratio. Furthermore, DEM suppressed cell migration and invasion by reversing EMT-related protein expression. RNA sequencing revealed that DEM primarily affected autophagy-related pathways, particularly through the PI3K/AKT signaling. DEM treatment led to an elevation in ROS generation and enhanced autophagic activity, as demonstrated by elevated LC3B puncta formation and autophagy-related protein expression. <em>In vivo</em>, DEM effectively suppressed tumor growth while showing a favorable safety profile.</div></div><div><h3>Conclusion</h3><div>This study provides comprehensive evidence that DEM exerts potent anti-tumor properties in OS via the PI3K/AKT pathway, highlighting the significance of DEM as a therapeutic candidate for OS.</div></div>","PeriodicalId":48806,"journal":{"name":"Journal of Bone Oncology","volume":"53 ","pages":"Article 100699"},"PeriodicalIF":3.4,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144480640","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}
Pub Date : 2025-06-17DOI: 10.1016/j.jbo.2025.100698
Nicolas Cristini , Mohamadreza Tavakoli , Mehdi Sanati , Saber Amin Yavari
Bone tissue serves as a perfect hosting site where metastatic cancer cells of the most prevalent cancer types, such as prostate and breast cancers, as well as the native bone sarcomas, can further proliferate, advancing the disease stage with the consequential decline of the patient’s prognosis. Understanding how the bone niche interacts with tumor cells and the mechanisms leading to drug resistance is a crucial step for enabling the identification of effective cancer therapies. Nevertheless, bone tumor research and the development of new effective anticancer drugs have been hampered for a long time due to the limitations of preclinical models. Traditional 2D cultures and animal models have failed to accurately replicate the human bone cancer microenvironment, driving researchers to develop 3D in vitro bone models using tissue-engineered bone constructs and advanced technologies like microfluidics and additive manufacturing. While a complete reproduction of the bone tumor microenvironment (TME), including all relevant cell types, stromal elements, and biophysical cues, remains elusive, targeted inclusion of key components has advanced the physiological relevance of these models. The following review evaluates the biomimetic approaches that have been used to recapitulate the bone TME through 3D in vitro models, with particular attention to recent studies aimed at more accurately mimicking the complexity of bone TME, highlighting future directions and the advancements required to overcome present limitations.
{"title":"Exploring bone-tumor interactions through 3D in vitro models: Implications for primary and metastatic cancers","authors":"Nicolas Cristini , Mohamadreza Tavakoli , Mehdi Sanati , Saber Amin Yavari","doi":"10.1016/j.jbo.2025.100698","DOIUrl":"10.1016/j.jbo.2025.100698","url":null,"abstract":"<div><div>Bone tissue serves as a perfect hosting site where metastatic cancer cells of the most prevalent cancer types, such as prostate and breast cancers, as well as the native bone sarcomas, can further proliferate, advancing the disease stage with the consequential decline of the patient’s prognosis. Understanding how the bone niche interacts with tumor cells and the mechanisms leading to drug resistance is a crucial step for enabling the identification of effective cancer therapies. Nevertheless, bone tumor research and the development of new effective anticancer drugs have been hampered for a long time due to the limitations of preclinical models. Traditional 2D cultures and animal models have failed to accurately replicate the human bone cancer microenvironment, driving researchers to develop 3D <em>in vitro</em> bone models using tissue-engineered bone constructs and advanced technologies like microfluidics and additive manufacturing. While a complete reproduction of the bone tumor microenvironment (TME), including all relevant cell types, stromal elements, and biophysical cues, remains elusive, targeted inclusion of key components has advanced the physiological relevance of these models. The following review evaluates the biomimetic approaches that have been used to recapitulate the bone TME through 3D <em>in vitro</em> models, with particular attention to recent studies aimed at more accurately mimicking the complexity of bone TME, highlighting future directions and the advancements required to overcome present limitations.</div></div>","PeriodicalId":48806,"journal":{"name":"Journal of Bone Oncology","volume":"53 ","pages":"Article 100698"},"PeriodicalIF":3.4,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144314338","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}
Pub Date : 2025-06-15DOI: 10.1016/j.jbo.2025.100697
Jun Teng , Yitong Ding , Can Liu , Yangfei Yi , Jie Wen , Sheng Xiao , Xiaohong Jian , Yufei Li
Chondroblastoma of the femoral head is a benign tumor originating from immature chondrocytes (chondroblasts), also known as Codman’s tumor. This tumor is mainly located in the epiphysis of the end of long bones, especially in the region of the femoral head. It is more common in children and adolescents. Its etiology is derived from embryonic cartilage, or mutations in chondroblasts. The diagnosis mainly depends on imaging examination and histopathological examination. Surgical resection is the main treatment method, and there are also many new methods such as gene therapy and immunotherapy. This article reviews the etiology, diagnosis and treatment of chondroblastoma of the femoral head, so as to provide ideas and basis for further clinical research on adolescent chondroblastoma of the femoral head.
{"title":"Chondroblastoma of the femoral head:current and future therapeutic options","authors":"Jun Teng , Yitong Ding , Can Liu , Yangfei Yi , Jie Wen , Sheng Xiao , Xiaohong Jian , Yufei Li","doi":"10.1016/j.jbo.2025.100697","DOIUrl":"10.1016/j.jbo.2025.100697","url":null,"abstract":"<div><div>Chondroblastoma of the femoral head is a benign tumor originating from immature chondrocytes (chondroblasts), also known as Codman’s tumor. This tumor is mainly located in the epiphysis of the end of long bones, especially in the region of the femoral head. It is more common in children and adolescents. Its etiology is derived from embryonic cartilage, or mutations in chondroblasts. The diagnosis mainly depends on imaging examination and histopathological examination. Surgical resection is the main treatment method, and there are also many new methods such as gene therapy and immunotherapy. This article reviews the etiology, diagnosis and treatment of chondroblastoma of the femoral head, so as to provide ideas and basis for further clinical research on adolescent chondroblastoma of the femoral head.</div></div>","PeriodicalId":48806,"journal":{"name":"Journal of Bone Oncology","volume":"53 ","pages":"Article 100697"},"PeriodicalIF":3.4,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144290499","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}
The clinical and radiological presentation of bone sarcomas in the proximal femur is often atypical, frequently leading to diagnostic errors or inappropriate treatments. To our knowledge, no previous studies have analyzed reasons for or compared outcomes among patients with proximal femoral bone sarcomas undergoing unplanned surgery.
Methods
Patients with proximal femoral bone sarcomas treated at our institution between January 2013 and January 2023 were retrospectively reviewed, including those initially misdiagnosed or mismanaged. Overall survival (OS) and event-free survival (EFS) rates were analyzed using Kaplan-Meier curves and log-rank tests. Independent-samples and paired t-tests were used to compare Musculoskeletal Tumor Society (MSTS) scores, while chi-square tests were used to assess local recurrence rates (LRR).
Results
Of the 85 patients included, 27 cases underwent unplanned surgery at external hospitals, including 16 males and 11 females, with a median age of 44 years (range: 11–81 years). Initial preoperative radiologic findings in these patients undergoing unplanned surgery showed no periosteal reaction or soft tissue mass. No significant differences in OS, EFS, or LRR were observed between the unplanned and planned surgery groups (p > 0.05). However, MSTS scores were significantly lower in the unplanned surgery group (p < 0.001).
Conclusion
Unplanned surgery correlates with poorer functional outcomes. Reducing its incidence requires not only improved diagnostic imaging but also increased clinical suspicion, adherence to standardized diagnostic protocols, and early referral to specialized sarcoma centers. A multidisciplinary approach by experienced teams may enhance diagnostic accuracy and surgical planning, thereby minimizing unplanned interventions.
{"title":"Long-term oncological and functional outcomes in patients with bone sarcomas in the proximal femur undergoing unplanned surgery: A single-center retrospective cohort study","authors":"Guodong Zhong , Tiao Lin , Yongqian Wang, Hao Yao, Aierxiding Aimaiti, Xianbiao Xie, Changye Zou, Junqiang Yin, Jingnan Shen, Gang Huang, Zhiqiang Zhao","doi":"10.1016/j.jbo.2025.100696","DOIUrl":"10.1016/j.jbo.2025.100696","url":null,"abstract":"<div><h3>Background</h3><div>The clinical and radiological presentation of bone sarcomas in the proximal femur is often atypical, frequently leading to diagnostic errors or inappropriate treatments. To our knowledge, no previous studies have analyzed reasons for or compared outcomes among patients with proximal femoral bone sarcomas undergoing unplanned surgery.</div></div><div><h3>Methods</h3><div>Patients with proximal femoral bone sarcomas treated at our institution between January 2013 and January 2023 were retrospectively reviewed, including those initially misdiagnosed or mismanaged. Overall survival (OS) and event-free survival (EFS) rates were analyzed using Kaplan-Meier curves and log-rank tests. Independent-samples and paired t-tests were used to compare Musculoskeletal Tumor Society (MSTS) scores, while chi-square tests were used to assess local recurrence rates (LRR).</div></div><div><h3>Results</h3><div>Of the 85 patients included, 27 cases underwent unplanned surgery at external hospitals, including 16 males and 11 females, with a median age of 44 years (range: 11–81 years). Initial preoperative radiologic findings in these patients undergoing unplanned surgery showed no periosteal reaction or soft tissue mass. No significant differences in OS, EFS, or LRR were observed between the unplanned and planned surgery groups (p > 0.05). However, MSTS scores were significantly lower in the unplanned surgery group (p < 0.001).</div></div><div><h3>Conclusion</h3><div>Unplanned surgery correlates with poorer functional outcomes. Reducing its incidence requires not only improved diagnostic imaging but also increased clinical suspicion, adherence to standardized diagnostic protocols, and early referral to specialized sarcoma centers. A multidisciplinary approach by experienced teams may enhance diagnostic accuracy and surgical planning, thereby minimizing unplanned interventions.</div></div>","PeriodicalId":48806,"journal":{"name":"Journal of Bone Oncology","volume":"53 ","pages":"Article 100696"},"PeriodicalIF":3.4,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321874","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}
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