Bone Research最新文献_第2页

Reprogramming to restore youthful epigenetics of senescent nucleus pulposus cells for mitigating intervertebral disc degeneration and alleviating low back pain

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-12 DOI: 10.1038/s41413-025-00416-1

Wenzheng Ma, Wantao Wang, Lei Zhao, Jinghao Fan, Lei Liu, Lin Huang, Baogan Peng, Jianru Wang, Baoshan Xu, Hongmei Liu, Decheng Wu, Zhaomin Zheng

{"title":"Reprogramming to restore youthful epigenetics of senescent nucleus pulposus cells for mitigating intervertebral disc degeneration and alleviating low back pain","authors":"Wenzheng Ma, Wantao Wang, Lei Zhao, Jinghao Fan, Lei Liu, Lin Huang, Baogan Peng, Jianru Wang, Baoshan Xu, Hongmei Liu, Decheng Wu, Zhaomin Zheng","doi":"10.1038/s41413-025-00416-1","DOIUrl":"https://doi.org/10.1038/s41413-025-00416-1","url":null,"abstract":"Aging is a pivotal risk factor for intervertebral disc degeneration (IVDD) and chronic low back pain (LBP). The restoration of aging nucleus pulposus cells (NPCs) to a youthful epigenetic state is crucial for IVDD treatment, but remains a formidable challenge. Here, we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes (Oct4, Klf4 and Sox2) in Cavin2-modified exosomes (OKS@M-Exo) for treatment of IVDD and alleviating LBP. The functional OKS@M-Exo efficaciously alleviated senescence markers (p16INK4a, p21CIP1 and p53), reduced DNA damage and H4K20me3 expression, as well as restored proliferation ability and metabolic balance in senescent NPCs, as validated through in vitro experiments. In a rat model of IVDD, OKS@M-Exo maintained intervertebral disc height, nucleus pulposus hydration and tissue structure, effectively ameliorated IVDD via decreasing the senescence markers. Additionally, OKS@M-Exo reduced nociceptive behavior and downregulated nociception markers, indicating its efficiency in alleviating LBP. The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation. Collectively, reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"14 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhanced SIRT3 expression restores mitochondrial quality control mechanism to reverse osteogenic impairment in type 2 diabetes mellitus 增强 SIRT3 的表达可恢复线粒体质量控制机制，从而逆转 2 型糖尿病患者的成骨障碍

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-03 DOI: 10.1038/s41413-024-00399-5

Yansi Xian, Bin Liu, Tao Shen, Lin Yang, Rui Peng, Hongdou Shen, Xueying An, Yutian Wang, Yu Ben, Qing Jiang, Baosheng Guo

{"title":"Enhanced SIRT3 expression restores mitochondrial quality control mechanism to reverse osteogenic impairment in type 2 diabetes mellitus","authors":"Yansi Xian, Bin Liu, Tao Shen, Lin Yang, Rui Peng, Hongdou Shen, Xueying An, Yutian Wang, Yu Ben, Qing Jiang, Baosheng Guo","doi":"10.1038/s41413-024-00399-5","DOIUrl":"https://doi.org/10.1038/s41413-024-00399-5","url":null,"abstract":"Osteoporosis represents a prevalent and debilitating comorbidity in patients diagnosed with type 2 diabetes mellitus (T2DM), which is characterized by suppressed osteoblast function and disrupted bone microarchitecture. In this study, we utilized male C57BL/6 J mice to investigate the role of SIRT3 in T2DM. Decreased SIRT3 expression and impaired mitochondrial quality control mechanism are observed in both in vitro and in vivo models of T2DM. Mechanistically, SIRT3 suppression results in hyperacetylation of FOXO3, hindering the activation of the PINK1/PRKN mediated mitophagy pathway and resulting in accumulation of dysfunctional mitochondria. Genetical overexpression or pharmacological activation of SIRT3 restores deacetylation status of FOXO3, thus facilitating mitophagy and ameliorating osteogenic impairment in T2DM. Collectively, our findings highlight the fundamental regulatory function of SIRT3 in mitochondrial quality control, crucial for maintaining bone homeostasis in T2DM. These insights not only enhance our understanding of the molecular mechanisms underlying diabetic osteoporosis but also identify SIRT3 as a promising therapeutic target for diabetic osteoporosis.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"36 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Beclin 1 of megakaryocytic lineage cells is locally dispensable for platelet hemostasis but functions distally in bone homeostasis 巨核细胞系细胞的 Beclin 1 在局部对血小板止血不起作用，但在远端对骨稳态起作用

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-03 DOI: 10.1038/s41413-025-00410-7

Lei Li, Chen Zhao, Ruizhi Zhang, Wen Wei, Bowen Liu, Jin Dong, Xueqin Gao, Di Zhang, Xueqing Wang, Meilin Lu, Yumu Zhang, Yao Yu, Na Yuan, Youjia Xu, Jianrong Wang, Yixuan Fang

{"title":"Beclin 1 of megakaryocytic lineage cells is locally dispensable for platelet hemostasis but functions distally in bone homeostasis","authors":"Lei Li, Chen Zhao, Ruizhi Zhang, Wen Wei, Bowen Liu, Jin Dong, Xueqin Gao, Di Zhang, Xueqing Wang, Meilin Lu, Yumu Zhang, Yao Yu, Na Yuan, Youjia Xu, Jianrong Wang, Yixuan Fang","doi":"10.1038/s41413-025-00410-7","DOIUrl":"https://doi.org/10.1038/s41413-025-00410-7","url":null,"abstract":"The crosstalk between megakaryocytic lineage cells and the skeletal system has just begun to be explored but remains largely elusive. Using conditional gene knockout mouse models, we demonstrated that loss of Beclin 1 (Becn1), a major regulator of mammalian autophagy, exclusively in the megakaryocytic lineage disrupted autophagy in platelets but did not compromise megakaryopoiesis or the formation and function of platelets. Unexpectedly, conditional Becn1 deletion in male mice led to a remarkable increase in bone mass with improved bone quality, in association with a decrease in sex hormone binding globulin (SHBG) and an increase in free testosterone (FT). In vivo Becn1 overexpression in megakaryocytic lineage-specific cells reduced bone mass and quality, along with an increase in SHBG and a decrease in FT. Transplantation of wild-type bone marrow cells into megakaryocytic lineage Becn1-deficient male mice restored bone mass and normalized SHBG and FT. Furthermore, bilateral orchiectomy of Becn1f/f;Pf4-iCre mice, which are crippled with the production of testosterone, resulted in a reduction in bone mass and quality, whereas in vivo overexpression of SHBG, specifically in the liver of Becn1f/f;Pf4-iCre mice, decreased FT and reduced bone mass and quality. In addition, metformin treatment, which induces SHBG expression, reduced FT and normalized bone mass in Becn1f/f;Pf4-iCre mice. We thus concluded that Becn1 of the megakaryocytic lineage is dispensable locally for platelet hemostasis but limits bone mass by increasing SHBG, which in turn reduces the FT of male mice. Our findings highlight a mechanism by which Becn1 from megakaryocytic lineage cells distally balances bone growth.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"84 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CD47 is required for mesenchymal progenitor proliferation and fracture repair

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-03 DOI: 10.1038/s41413-025-00409-0

Robert L. Zondervan, Christina A. Capobianco, Daniel C. Jenkins, John D. Reicha, Livia Fredrick, Charles Lam, Jeanna T. Schmanski, Jeffery S. Isenberg, Jaimo Ahn, Ralph S. Marcucio, Kurt D. Hankenson

{"title":"CD47 is required for mesenchymal progenitor proliferation and fracture repair","authors":"Robert L. Zondervan, Christina A. Capobianco, Daniel C. Jenkins, John D. Reicha, Livia Fredrick, Charles Lam, Jeanna T. Schmanski, Jeffery S. Isenberg, Jaimo Ahn, Ralph S. Marcucio, Kurt D. Hankenson","doi":"10.1038/s41413-025-00409-0","DOIUrl":"https://doi.org/10.1038/s41413-025-00409-0","url":null,"abstract":"CD47 is a ubiquitous and pleiotropic cell-surface receptor. Disrupting CD47 enhances injury repair in various tissues but the role of CD47 has not been studied in bone injuries. In a murine closed-fracture model, CD47-null mice showed decreased callus bone formation as assessed by microcomputed tomography 10 days post-fracture and increased fibrous volume as determined by histology. To understand the cellular basis for this phenotype, mesenchymal progenitors (MSC) were harvested from bone marrow. CD47-null MSC showed decreased large fibroblast colony formation (CFU-F), significantly less proliferation, and fewer cells in S-phase, although osteoblast differentiation was unaffected. However, consistent with prior research, CD47-null endothelial cells showed increased proliferation relative to WT cells. Similarly, in a murine ischemic fracture model, CD47-null mice showed reduced fracture callus size due to a reduction in bone relative to WT 15 days-post fracture. Consistent with our in vitro results, in vivo EdU labeling showed decreased cell proliferation in the callus of CD47-null mice, while staining for CD31 and endomucin demonstrated increased endothelial cell density. Finally, WT mice with ischemic fracture that were administered a CD47 morpholino, which blocks CD47 protein production, showed a callus phenotype similar to that of ischemic fractures in CD47-null mice, suggesting the phenotype was not due to developmental changes in the knockout mice. Thus, inhibition of CD47 during bone healing reduces both non-ischemic and ischemic fracture healing, in part, by decreasing MSC proliferation. Furthermore, the increase in endothelial cell proliferation and early blood vessel density caused by CD47 disruption is not sufficient to overcome MSC dysfunction.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"130 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Apolipoprotein E is a marker of all chondrocytes in the growth plate resting zone

IF 12.7 1区医学

Bone Research Pub Date : 2025-03-03 DOI: 10.1038/s41413-025-00407-2

Joe Kodama, Takeshi Oichi, Kevin J. Wilkinson, Joshua M. Abzug, Takashi Kaito, Motomi Enomoto-Iwamoto, Masahiro Iwamoto, Satoru Otsuru

{"title":"Apolipoprotein E is a marker of all chondrocytes in the growth plate resting zone","authors":"Joe Kodama, Takeshi Oichi, Kevin J. Wilkinson, Joshua M. Abzug, Takashi Kaito, Motomi Enomoto-Iwamoto, Masahiro Iwamoto, Satoru Otsuru","doi":"10.1038/s41413-025-00407-2","DOIUrl":"https://doi.org/10.1038/s41413-025-00407-2","url":null,"abstract":"The resting zone (RZ) in mammalian growth plates is critical for maintaining and regulating chondrocyte turnover during longitudinal bone growth as a control tower and stem cell reservoir. Although recent lineage tracing studies have identified several markers for stem cells in the RZ, these markers only partially label chondrocytes in the RZ, suggesting that the resting chondrocytes (RCs) are a heterogeneous population with different types of stem cells. Since a comprehensive marker for RCs is still lacking, the RZ is generally determined based on ambiguous histological criteria, such as small and round chondrocytes without columnar formation, which may lead to inconsistencies among researchers. Therefore, in this study, we used single-cell RNA sequencing (scRNAseq) of growth plate chondrocytes followed by validation by fluorescence in situ hybridization (FISH) to precisely annotate cell clusters in scRNAseq and search for a marker of RCs. The scRNAseq analysis revealed that apolipoprotein E (Apoe) was the top-hit gene, which was ubiquitously expressed in the RC cluster. FISH confirmed that Apoe was exclusively localized to the histologically defined RZ. In newly generated ApoemCherry knock-in mice, we further confirmed that mCherry expression mirrored the distribution of Apoe-expressing chondrocytes in the RZ particularly after the formation of the secondary ossification center. These mCherry+ RCs were slow cycling in vivo and exhibited stem cell properties in vitro. Moreover, APOE was detected in human growth plate RCs. These findings suggest that apolipoprotein E is a novel pan-RC marker in both mouse and human growth plates.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"5 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bifidobacterium animalis subsp. lactis A6 ameliorates bone and muscle loss via modulating gut microbiota composition and enhancing butyrate production

IF 12.7 1区医学

Bone Research Pub Date : 2025-02-25 DOI: 10.1038/s41413-024-00381-1

Ming Chen, Yi Li, Zhengyuan Zhai, Hui Wang, Yuan Lin, Feifan Chang, Siliang Ge, Xinyu Sun, Wei Wei, Duanyang Wang, Mingming Zhang, Ruijing Chen, Haikuan Yu, Taojin Feng, Xiang Huang, Dongliang Cheng, Jiang Liu, Wenxuan Di, Yanling Hao, Pengbin Yin, Peifu Tang

{"title":"Bifidobacterium animalis subsp. lactis A6 ameliorates bone and muscle loss via modulating gut microbiota composition and enhancing butyrate production","authors":"Ming Chen, Yi Li, Zhengyuan Zhai, Hui Wang, Yuan Lin, Feifan Chang, Siliang Ge, Xinyu Sun, Wei Wei, Duanyang Wang, Mingming Zhang, Ruijing Chen, Haikuan Yu, Taojin Feng, Xiang Huang, Dongliang Cheng, Jiang Liu, Wenxuan Di, Yanling Hao, Pengbin Yin, Peifu Tang","doi":"10.1038/s41413-024-00381-1","DOIUrl":"https://doi.org/10.1038/s41413-024-00381-1","url":null,"abstract":"Systematic bone and muscle loss is a complex metabolic disease, which is frequently linked to gut dysfunction, yet its etiology and treatment remain elusive. While probiotics show promise in managing diseases through microbiome modulation, their therapeutic impact on gut dysfunction-induced bone and muscle loss remains to be elucidated. Employing dextran sulfate sodium (DSS)-induced gut dysfunction model and wide-spectrum antibiotics (ABX)-treated mice model, our study revealed that gut dysfunction instigates muscle and bone loss, accompanied by microbial imbalances. Importantly, Bifidobacterium animalis subsp. lactis A6 (B. lactis A6) administration significantly ameliorated muscle and bone loss by modulating gut microbiota composition and enhancing butyrate-producing bacteria. This intervention effectively restored depleted butyrate levels in serum, muscle, and bone tissues caused by gut dysfunction. Furthermore, butyrate supplementation mitigated musculoskeletal loss by repairing the damaged intestinal barrier and enriching beneficial butyrate-producing bacteria. Importantly, butyrate inhibited the NF-κB pathway activation, and reduced the secretion of corresponding inflammatory factors in T cells. Our study highlights the critical role of dysbiosis in gut dysfunction-induced musculoskeletal loss and underscores the therapeutic potential of B. lactis A6. These discoveries offer new microbiome directions for translational and clinical research, providing promising strategies for preventing and managing musculoskeletal diseases.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"31 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects

IF 12.7 1区医学

Bone Research Pub Date : 2025-02-25 DOI: 10.1038/s41413-024-00398-6

Qin Ru, Yusheng Li, Xi Zhang, Lin Chen, Yuxiang Wu, Junxia Min, Fudi Wang

{"title":"Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects","authors":"Qin Ru, Yusheng Li, Xi Zhang, Lin Chen, Yuxiang Wu, Junxia Min, Fudi Wang","doi":"10.1038/s41413-024-00398-6","DOIUrl":"https://doi.org/10.1038/s41413-024-00398-6","url":null,"abstract":"The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"27 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting AKT as a promising strategy for SOX2-positive, chemoresistant osteosarcoma 靶向 AKT 是治疗 SOX2 阳性、化疗耐药骨肉瘤的有效策略

IF 12.7 1区医学

Bone Research Pub Date : 2025-02-24 DOI: 10.1038/s41413-024-00395-9

Yujie Liu, Li Kang, Jing Luo, Minglei Yang, Da Wang, Juelan Ye, Xinghai Yang, Wei Wan, Jiemin Wong, Jianru Xiao

{"title":"Targeting AKT as a promising strategy for SOX2-positive, chemoresistant osteosarcoma","authors":"Yujie Liu, Li Kang, Jing Luo, Minglei Yang, Da Wang, Juelan Ye, Xinghai Yang, Wei Wan, Jiemin Wong, Jianru Xiao","doi":"10.1038/s41413-024-00395-9","DOIUrl":"https://doi.org/10.1038/s41413-024-00395-9","url":null,"abstract":"Osteosarcoma (OS) is the most prevalent type of primary malignant bone cancer and currently lacks effective targeted treatments. Increasing evidence indicates that SOX2 overexpression is a primary driver of OS. By screening a small-molecule kinase inhibitor library, we identified AKT as a kinase essential for robust SOX2 expression in OS cells. AKT was found to be frequently overexpressed in OS and positively correlated with SOX2 protein levels. We demonstrated that AKT has no effect on SOX2 transcription but promotes SOX2 protein stability. Mechanistically, AKT binds to and phosphorylates SOX2 at T116, preventing SOX2 ubiquitination and proteasome-dependent degradation by ubiquitin E3 ligases UBR5 and STUB1. Moreover, we found that AKT-SOX2 axis is a significant modulator of cancer stemness and chemoresistance and that the combination of AKT inhibitor MK2206 and cisplatin resulted in a synergistic and potent inhibition of OS tumor growth in the PDX model. In conclusion, we identified a critical role for AKT in promoting SOX2 overexpression, tumor stemness, and chemoresistance in OS, and provided evidence that targeting AKT combined with chemotherapy may hold promise for treating refractory OS.<figure>Working model showing that AKT stabilizes SOX2 by phosphorylating T116 site. Phosphorylation by AKT restraints the binding and ubiquitinoylation of SOX2 by the UBR5 and STUB1, thus promoting SOX2 stability and tumorigenic activity. Targeting AKT by MK2206 inhibits T116 phosphorylation and promotes SOX2 ubiquitination pathway, which impairs SOX2 tumorigenic activity. A combined treatment with chemo reagent and AKT inhibitor could achieve better therapeutic effect for SOX2-positive OS.</figure>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"30 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CCN2 mediates fibroblast-macrophage interaction in knee arthrofibrosis based on single-cell RNA-seq analysis 基于单细胞RNA-seq分析的CCN2在膝关节纤维化中介导成纤维细胞与巨噬细胞的相互作用

IF 12.7 1区医学

Bone Research Pub Date : 2025-02-24 DOI: 10.1038/s41413-025-00400-9

Ziyun Li, Jia Jiang, Kangwen Cai, Yi Qiao, Xuancheng Zhang, Liren Wang, Yuhao Kang, Xiulin Wu, Benpeng Zhao, Xiuli Wang, Tianyi Zhang, Zhiqi Lin, Jinlong Wu, Simin Lu, Haihan Gao, Haocheng Jin, Caiqi Xu, Xiaoqiao Huangfu, Zhengzhi James, Qiuhua Chen, Xiaoqi Zheng, Ning-Ning Liu, Jinzhong Zhao

{"title":"CCN2 mediates fibroblast-macrophage interaction in knee arthrofibrosis based on single-cell RNA-seq analysis","authors":"Ziyun Li, Jia Jiang, Kangwen Cai, Yi Qiao, Xuancheng Zhang, Liren Wang, Yuhao Kang, Xiulin Wu, Benpeng Zhao, Xiuli Wang, Tianyi Zhang, Zhiqi Lin, Jinlong Wu, Simin Lu, Haihan Gao, Haocheng Jin, Caiqi Xu, Xiaoqiao Huangfu, Zhengzhi James, Qiuhua Chen, Xiaoqi Zheng, Ning-Ning Liu, Jinzhong Zhao","doi":"10.1038/s41413-025-00400-9","DOIUrl":"https://doi.org/10.1038/s41413-025-00400-9","url":null,"abstract":"Knee arthrofibrosis, characterized by excessive matrix protein production and deposition, substantially impairs basic daily functions, causing considerable distress and financial burden. However, the underlying pathomechanisms remain unclear. Here, we characterized the heterogeneous cell populations and cellular pathways by combination of flow cytometry and single-cell RNA-seq analysis of synovial tissues from six patients with or without knee arthrofibrosis. Increased macrophages and fibroblasts were observed with decreased numbers of fibroblast-like synoviocytes, endothelial cells, vascular smooth muscle cells, and T cells in the arthrofibrosis group compared with negative controls. Notably, fibroblasts were discovered to interact with macrophages, and lead to fibrosis through TGF-β pathway induced CCN2 expression in fibroblasts. CCN2 was demonstrated to be required for fibroblast pro-fibrotic functions (activation, proliferation, and migration) through TGFBR/SMAD pathway. The expression of CCN2 was positively correlated with the collagen volume and TGF-β expression and negatively associated with patient-reported outcome measures in another cohort of patients with knee arthrofibrosis. Our study reveals the role of CCN2 in the fibroblast-macrophage interaction through TGF-β pathway which might help to shed light on CCN2 as a potential biomarker.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"66 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

3D imaging reveals changes in the neurovascular architecture of the murine calvarium with aging

IF 12.7 1区医学

Bone Research Pub Date : 2025-02-21 DOI: 10.1038/s41413-025-00401-8

Allison L. Horenberg, Yunke Ren, Eric Z. Zeng, Alexandra N. Rindone, Arvind P. Pathak, Warren L. Grayson

{"title":"3D imaging reveals changes in the neurovascular architecture of the murine calvarium with aging","authors":"Allison L. Horenberg, Yunke Ren, Eric Z. Zeng, Alexandra N. Rindone, Arvind P. Pathak, Warren L. Grayson","doi":"10.1038/s41413-025-00401-8","DOIUrl":"https://doi.org/10.1038/s41413-025-00401-8","url":null,"abstract":"Calvarial nerves, along with vasculature, influence skull formation during development and following injury, but it remains unclear how calvarial nerves are spatially distributed during postnatal growth and aging. Studying the spatial distribution of nerves in the skull remains a challenge due to a lack of methods to quantify 3D structures in intact bone. To visualize calvarial 3D neurovascular architecture, we imaged nerves and endothelial cells with lightsheet microscopy. We employed machine-learning-based segmentation to facilitate high-resolution characterization from post-natal day 0 (P0) to 80 weeks. We found that TUBB3+ nerve density decreased with aging with the frontal bone demonstrating earlier onset age-related nerve loss than the parietal bone. In addition, nerves in the periosteum and dura mater exhibited similar yet distinct temporal patterns of nerve growth and loss. While no difference was observed in TUBB3+ nerves during skeletal maturation (P0 → 12 weeks), we did observe an increase in the volume of unmyelinated nerves in the dura mater. Regarding calvarial vasculature, larger CD31hiEmcn- vessel fraction increased with aging, while CD31hiEmcnhi vessel fraction was reduced. Throughout all ages, calvarial nerves maintained a preferential spatial association with CD31hiEmcnhi vessels, however, this association decreased with aging. Additionally, we used a model of Apert syndrome to explore the impact of suture-related disease on neurovascular architecture. Collectively, this 3D, spatiotemporal characterization of calvarial nerves throughout the lifespan and provides new insights into age-induced neurovascular architecture.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"6 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0