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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":"<p>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 <i>CCN2</i> 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.</p>","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":"<p>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<sup>+</sup> 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<sup>+</sup> 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 CD31<sup>hi</sup>Emcn<sup>-</sup> vessel fraction increased with aging, while CD31<sup>hi</sup>Emcn<sup>hi</sup> vessel fraction was reduced. Throughout all ages, calvarial nerves maintained a preferential spatial association with CD31<sup>hi</sup>Emcn<sup>hi</sup> 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.</p>","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
Matrix stiffness regulates nucleus pulposus cell glycolysis by MRTF-A-dependent mechanotransduction
IF 12.7 1区 医学
Bone Research Pub Date : 2025-02-14 DOI: 10.1038/s41413-025-00402-7
Haoran Xu, Kang Wei, Jinhao Ni, Xiaofeng Deng, Yuexing Wang, Taiyang Xiang, Fanglong Song, Qianliang Wang, Yanping Niu, Fengxian Jiang, Jun Wang, Lei Sheng, Jun Dai
{"title":"Matrix stiffness regulates nucleus pulposus cell glycolysis by MRTF-A-dependent mechanotransduction","authors":"Haoran Xu, Kang Wei, Jinhao Ni, Xiaofeng Deng, Yuexing Wang, Taiyang Xiang, Fanglong Song, Qianliang Wang, Yanping Niu, Fengxian Jiang, Jun Wang, Lei Sheng, Jun Dai","doi":"10.1038/s41413-025-00402-7","DOIUrl":"https://doi.org/10.1038/s41413-025-00402-7","url":null,"abstract":"<p>Increased matrix stiffness of nucleus pulposus (NP) tissue is a main feature of intervertebral disc degeneration (IVDD) and affects various functions of nucleus pulposus cells (NPCs). Glycolysis is the main energy source for NPC survival, but the effects and underlying mechanisms of increased extracellular matrix (ECM) stiffness on NPC glycolysis remain unknown. In this study, hydrogels with different stiffness were established to mimic the mechanical environment of NPCs. Notably, increased matrix stiffness in degenerated NP tissues from IVDD patients was accompanied with impaired glycolysis, and NPCs cultured on rigid substrates exhibited a reduction in glycolysis. Meanwhile, RNA sequencing analysis showed altered cytoskeleton-related gene expression in NPCs on rigid substrates. Myocardin-related transcription factor A (MRTF-A) is a transcriptional coactivator in mechanotransduction mainly responding to cytoskeleton remodeling, which was activated and translocated to the nucleus under rigid substrate and was upregulated during IVDD progression. Furthermore, gas chromatography-mass spectrometry (GC-MS) analysis revealed that MRTF-A overexpression reduced NPC glycolytic metabolite abundance and identified a correlation with AMPK pathway. Mechanistically, rigid substrates and MRTF-A overexpression inhibited Kidins220 expression and AMPK phosphorylation in NPCs, whereas MRTF-A inhibition, treated with the MRTF-A inhibitor CCG, partially rescued NP tissue degeneration and glycolytic enzyme expression. Our data demonstrate that MRTF-A is a critical regulator that responds to increased matrix stiffness in IVDD, and MRTF-A activation reduces NPC glycolysis by down-regulating Kidins220 and inhibiting AMPK phosphorylation.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"66 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417421","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
Photothermal sensitive nanocomposite hydrogel for infectious bone defects
IF 12.7 1区 医学
Bone Research Pub Date : 2025-02-14 DOI: 10.1038/s41413-024-00377-x
Yanting Wu, Xi Xie, Guowen Luo, Jing Xie, Xiuwen Ye, Wanrong Gu, Anchun Mo, Zhiyong Qian, Chenchen Zhou, Jinfeng Liao
{"title":"Photothermal sensitive nanocomposite hydrogel for infectious bone defects","authors":"Yanting Wu, Xi Xie, Guowen Luo, Jing Xie, Xiuwen Ye, Wanrong Gu, Anchun Mo, Zhiyong Qian, Chenchen Zhou, Jinfeng Liao","doi":"10.1038/s41413-024-00377-x","DOIUrl":"https://doi.org/10.1038/s41413-024-00377-x","url":null,"abstract":"<p>Infectious bone defects represent a substantial challenge in clinical practice, necessitating the deployment of advanced therapeutic strategies. This study presents a treatment modality that merges a mild photothermal therapy hydrogel with a pulsed drug delivery mechanism. The system is predicated on a hydrogel matrix that is thermally responsive, characteristic of bone defect sites, facilitating controlled and site-specific drug release. The cornerstone of this system is the incorporation of mild photothermal nanoparticles, which are activated within the temperature range of 40–43 °C, thereby enhancing the precision and efficacy of drug delivery. Our findings demonstrate that the photothermal response significantly augments the localized delivery of therapeutic agents, mitigating systemic side effects and bolstering efficacy at the defect site. The synchronized pulsed release, cooperated with mild photothermal therapy, effectively addresses infection control, and promotes bone regeneration. This approach signifies a considerable advancement in the management of infectious bone defects, offering an effective and patient-centric alternative to traditional methods. Our research endeavors to extend its applicability to a wider spectrum of tissue regeneration scenarios, underscoring its transformative potential in the realm of regenerative medicine.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"28 12 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417422","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
Golgi-restored vesicular replenishment retards bone aging and empowers aging bone regeneration 高尔基恢复囊泡补充可延缓骨质老化并促进老化骨再生
IF 12.7 1区 医学
Bone Research Pub Date : 2025-02-08 DOI: 10.1038/s41413-024-00386-w
Peisheng Liu, Hao Guo, Xiaoyao Huang, Anqi Liu, Ting Zhu, Chenxi Zheng, Fei Fu, Kaichao Zhang, Shijie Li, Xinyan Luo, Jiongyi Tian, Yan Jin, Kun Xuan, Bingdong Sui
{"title":"Golgi-restored vesicular replenishment retards bone aging and empowers aging bone regeneration","authors":"Peisheng Liu, Hao Guo, Xiaoyao Huang, Anqi Liu, Ting Zhu, Chenxi Zheng, Fei Fu, Kaichao Zhang, Shijie Li, Xinyan Luo, Jiongyi Tian, Yan Jin, Kun Xuan, Bingdong Sui","doi":"10.1038/s41413-024-00386-w","DOIUrl":"https://doi.org/10.1038/s41413-024-00386-w","url":null,"abstract":"<p>Healthy aging is a common goal for humanity and society, and one key to achieving it is the rejuvenation of senescent resident stem cells and empowerment of aging organ regeneration. However, the mechanistic understandings of stem cell senescence and the potential strategies to counteract it remain elusive. Here, we reveal that the aging bone microenvironment impairs the Golgi apparatus thus diminishing mesenchymal stem cell (MSC) function and regeneration. Interestingly, replenishment of cell aggregates-derived extracellular vesicles (CA-EVs) rescues Golgi dysfunction and empowers senescent MSCs through the Golgi regulatory protein Syntaxin 5. Importantly, in vivo administration of CA-EVs significantly enhanced the bone defect repair rate and improved bone mass in aging mice, suggesting their therapeutic value for treating age-related osteoporosis and promoting bone regeneration. Collectively, our findings provide insights into Golgi regulation in stem cell senescence and bone aging, which further highlight CA-EVs as a potential rejuvenative approach for aging bone regeneration.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"48 20 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367477","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
Nuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2
IF 12.7 1区 医学
Bone Research Pub Date : 2025-01-30 DOI: 10.1038/s41413-024-00394-w
Qi Dong, Haoyuan Fu, Wenxiao Li, Xinyu Ji, Yingchao Yin, Yiran Zhang, Yanbo Zhu, Guoqiang Li, Huiyang Jia, Heng Zhang, Haofei Wang, Jinglue Hu, Ganggang Wang, Zhihao Wu, Yingze Zhang, Sujuan Xu, Zhiyong Hou
{"title":"Nuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2","authors":"Qi Dong, Haoyuan Fu, Wenxiao Li, Xinyu Ji, Yingchao Yin, Yiran Zhang, Yanbo Zhu, Guoqiang Li, Huiyang Jia, Heng Zhang, Haofei Wang, Jinglue Hu, Ganggang Wang, Zhihao Wu, Yingze Zhang, Sujuan Xu, Zhiyong Hou","doi":"10.1038/s41413-024-00394-w","DOIUrl":"https://doi.org/10.1038/s41413-024-00394-w","url":null,"abstract":"<p>The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis. Nuclear receptors (NRs) are now understood to be crucial in bone physiology and pathology. However, the function of the Farnesoid X receptor (FXR), a member of the NR family, in regulating bone homeostasis remains incompletely understood. In this study, in vitro and in vivo models revealed delayed bone development and an osteoporosis phenotype in mice lacking FXR in bone marrow mesenchymal stem cells (BMSCs) and osteoblasts due to impaired osteoblast differentiation. Mechanistically, FXR could stabilize RUNX2 by inhibiting Thoc6-mediated ubiquitination, thereby promoting osteogenic activity in BMSCs. Moreover, activated FXR could directly bind to the Thoc6 promoter, suppressing its expression. The interaction between RUNX2 and Thoc6 was mediated by the Runt domain of RUNX2 and the WD repeat of Thoc6. Additionally, Obeticholic acid (OCA), an orally available FXR agonist, could ameliorate bone loss in an ovariectomy (OVX)-induced osteoporotic mouse model. Taken together, our findings suggest that FXR plays pivotal roles in osteoblast differentiation by regulating RUNX2 stability and that targeting FXR may be a promising therapeutic approach for osteoporosis.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"4 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056500","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
Signaling pathway mechanisms of circadian clock gene Bmal1 regulating bone and cartilage metabolism: a review
IF 12.7 1区 医学
Bone Research Pub Date : 2025-01-27 DOI: 10.1038/s41413-025-00403-6
Yiting Ze, Yongyao Wu, Zhen Tan, Rui Li, Rong Li, Wenzhen Gao, Qing Zhao
{"title":"Signaling pathway mechanisms of circadian clock gene Bmal1 regulating bone and cartilage metabolism: a review","authors":"Yiting Ze, Yongyao Wu, Zhen Tan, Rui Li, Rong Li, Wenzhen Gao, Qing Zhao","doi":"10.1038/s41413-025-00403-6","DOIUrl":"https://doi.org/10.1038/s41413-025-00403-6","url":null,"abstract":"<p>Circadian rhythm is ubiquitous in nature. Circadian clock genes such as <i>Bmal1</i> and <i>Clock</i> form a multi-level transcription-translation feedback network, and regulate a variety of physiological and pathological processes, including bone and cartilage metabolism. Deletion of the core clock gene <i>Bmal1</i> leads to pathological bone alterations, while the phenotypes are not consistent. Studies have shown that multiple signaling pathways are involved in the process of <i>Bmal1</i> regulating bone and cartilage metabolism, but the exact regulatory mechanisms remain unclear. This paper reviews the signaling pathways by which <i>Bmal1</i> regulates bone/cartilage metabolism, the upstream regulatory factors that control <i>Bmal1</i>, and the current <i>Bmal1</i> knockout mouse models for research. We hope to provide new insights for the prevention and treatment of bone/cartilage diseases related to circadian rhythms.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"7 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049743","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
Isovitexin targets SIRT3 to prevent steroid-induced osteonecrosis of the femoral head by modulating mitophagy-mediated ferroptosis 异维菌素以SIRT3为靶点,通过调节有丝分裂介导的铁蛋白沉积,预防类固醇诱发的股骨头坏死
IF 12.7 1区 医学
Bone Research Pub Date : 2025-01-26 DOI: 10.1038/s41413-024-00390-0
Yinuo Fan, Zhiwen Chen, Haixing Wang, Mengyu Jiang, Hongduo Lu, Yangwenxiang Wei, Yunhao Hu, Liang Mo, Yuhao Liu, Chi Zhou, Wei He, Zhenqiu Chen
{"title":"Isovitexin targets SIRT3 to prevent steroid-induced osteonecrosis of the femoral head by modulating mitophagy-mediated ferroptosis","authors":"Yinuo Fan, Zhiwen Chen, Haixing Wang, Mengyu Jiang, Hongduo Lu, Yangwenxiang Wei, Yunhao Hu, Liang Mo, Yuhao Liu, Chi Zhou, Wei He, Zhenqiu Chen","doi":"10.1038/s41413-024-00390-0","DOIUrl":"https://doi.org/10.1038/s41413-024-00390-0","url":null,"abstract":"<p>The death of osteoblasts induced by glucocorticoid (GC)-mediated oxidative stress plays a crucial role in the development of steroid-induced osteonecrosis of the femoral head (SIONFH). Improving bone formation driven by osteoblasts has shown promising outcomes in the prognosis of SIONFH. Isovitexin has demonstrated antioxidant properties, but its therapeutic effects on GC-induced oxidative stress and SIONFH remain unexplored. In this study, we analyzed clinical samples obtained from SIONFH patients using proteomic and bioinformatic approaches. We found an imbalance in mitochondrial homeostasis and ferroptosis-induced impairment of osteogenic capacity in SIONFH. Subsequently, we investigated the cause-and-effect relationship between mitochondria and ferroptosis, as well as the regulatory role of mitophagy in maintaining mitochondrial homeostasis and controlling ferroptosis. We then identified the critical involvement of SIRT3 in modulating mitochondrial homeostasis and ferroptosis. Furthermore, molecular docking and co-immunoprecipitation confirmed the strong interaction between SIRT3 and BNIP3. Strikingly, restoring SIRT3 expression significantly inhibited pathological mitophagy mediated by the BNIP3/NIX pathway. Additionally, we discovered that Isovitexin, by promoting SIRT3 expression, effectively regulated mitophagy, preserved mitochondrial homeostasis in osteoblasts, suppressed ferroptosis, and restored osteogenic capacity, leading to remarkable improvements in SIONFH. These findings reveal the effects and molecular mechanisms of Isovitexin on SIONFH and highlight the potential of targeting SIRT3 as a promising strategy to suppress mitophagy-mediated ferroptosis in osteoblasts and against SIONFH.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"44 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034997","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
Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation
IF 12.7 1区 医学
Bone Research Pub Date : 2025-01-26 DOI: 10.1038/s41413-024-00393-x
Mohammad Alhashmi, Abdulrahman M. E. Gremida, Santosh K. Maharana, Marco Antonaci, Amy Kerr, Shijian Fu, Sharna Lunn, David A. Turner, Noor A. Al-Maslamani, Ke Liu, Maria M. Meschis, Hazel Sutherland, Peter Wilson, Peter Clegg, Grant N. Wheeler, Robert J. van ‘t Hof, George Bou-Gharios, Kazuhiro Yamamoto
{"title":"Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation","authors":"Mohammad Alhashmi, Abdulrahman M. E. Gremida, Santosh K. Maharana, Marco Antonaci, Amy Kerr, Shijian Fu, Sharna Lunn, David A. Turner, Noor A. Al-Maslamani, Ke Liu, Maria M. Meschis, Hazel Sutherland, Peter Wilson, Peter Clegg, Grant N. Wheeler, Robert J. van ‘t Hof, George Bou-Gharios, Kazuhiro Yamamoto","doi":"10.1038/s41413-024-00393-x","DOIUrl":"https://doi.org/10.1038/s41413-024-00393-x","url":null,"abstract":"<p>Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip, osteoporosis and osteoarthritis. Our work addresses the critical question of how these skeletal pathologies emerge. Here, we show the abundant expression of LRP1 in skeletal progenitor cells at mouse embryonic stage E10.5 and onwards, especially in the perichondrium, the stem cell layer surrounding developing limbs essential for bone formation. <i>Lrp1</i> deficiency in these stem cells causes joint fusion, malformation of cartilage/bone template and markedly delayed or lack of primary ossification. These abnormalities, which resemble phenotypes associated with Wnt signalling pathways, result in severe and persistent skeletal defects including a severe deficit in hip joint and patella, and markedly deformed and low-density long bones leading to dwarfism and impaired mobility. Mechanistically, we show that LRP1 regulates core non-canonical Wnt/planar cell polarity (PCP) components that may explain the malformation of long bones. LRP1 directly binds to Wnt5a, facilitates its cell-association and endocytic degradation and recycling. In the developing limbs, LRP1 partially colocalises with Wnt5a and its deficiency alters abundance and distribution of Wnt5a and Vangl2. Finally, using <i>Xenopus</i> as a model system, we show the regulatory role for LRP1 in Wnt/PCP signalling. We propose that in skeletal progenitors, LRP1 plays a critical role in formation and maturity of multiple bones and joints by regulating Wnt signalling, providing novel insights into the fundamental processes of morphogenesis and the emergence of skeletal pathologies.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"47 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034998","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
Enhancer-driven Shh signaling promotes glia-to-mesenchyme transition during bone repair
IF 12.7 1区 医学
Bone Research Pub Date : 2025-01-26 DOI: 10.1038/s41413-024-00396-8
Xin Shen, Hang Zhang, Zesheng Song, Yangjiele Dong, Xiao Ge, Shenghao Jin, Songsong Guo, Ping Zhang, Yu Fu, Yuchi Zhu, Na Xiao, Dongmiao Wang, Jie Cheng, Rongyao Xu, Hongbing Jiang
{"title":"Enhancer-driven Shh signaling promotes glia-to-mesenchyme transition during bone repair","authors":"Xin Shen, Hang Zhang, Zesheng Song, Yangjiele Dong, Xiao Ge, Shenghao Jin, Songsong Guo, Ping Zhang, Yu Fu, Yuchi Zhu, Na Xiao, Dongmiao Wang, Jie Cheng, Rongyao Xu, Hongbing Jiang","doi":"10.1038/s41413-024-00396-8","DOIUrl":"https://doi.org/10.1038/s41413-024-00396-8","url":null,"abstract":"<p>Plp1-lineage Schwann cells (SCs) of peripheral nerve play a critical role in vascular remodeling and osteogenic differentiation during the early stage of bone healing, and the abnormal plasticity of SCs would jeopardize the bone regeneration. However, how Plp1-lineage cells respond to injury and initiate the vascularized osteogenesis remains incompletely understood. Here, by employing single-cell transcriptional profiling combined with lineage-specific tracing models, we uncover that Plp1-lineage cells undergoing injury-induced glia-to-MSCs transition contributed to osteogenesis and revascularization in the initial stage of bone injury. Importantly, our data demonstrated that the Sonic hedgehog (Shh) signaling was responsible for the transition process initiation, which was strongly activated by c-Jun/SIRT6/BAF170 complex-driven <i>Shh</i> enhancers. Collectively, these findings depict an injury-specific niche signal-mediated Plp1-lineage cells transition towards Gli1<sup>+</sup> MSCs and may be instructive for approaches to promote bone regeneration during aging or other bone diseases.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"16 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034999","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
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