Bone Research最新文献_第3页

Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation 盘状蛋白结构域受体2是异位骨形成过程中BMP信号的重要调节剂

IF 12.7 1区医学

Bone Research Pub Date : 2025-01-02 DOI: 10.1038/s41413-024-00391-z

Fashuai Wu, Chunxi Ge, Haichun Pan, Yuanyuan Han, Yuji Mishina, Vesa Kaartinen, Renny T. Franceschi

{"title":"Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation","authors":"Fashuai Wu, Chunxi Ge, Haichun Pan, Yuanyuan Han, Yuji Mishina, Vesa Kaartinen, Renny T. Franceschi","doi":"10.1038/s41413-024-00391-z","DOIUrl":"https://doi.org/10.1038/s41413-024-00391-z","url":null,"abstract":"Bone morphogenetic proteins are essential for bone regeneration/fracture healing but can also induce heterotopic ossification (HO). Understanding accessory factors modulating BMP signaling would provide both a means of enhancing BMP-dependent regeneration while preventing HO. This study focuses on the ability of the collagen receptor, discoidin domain receptor 2 (DDR2), to regulate BMP activity. As will be shown, induction of bone formation by subcutaneous BMP2 implants is severely compromised in Ddr2-deficient mice. In addition, Ddr2 deficiency attenuates HO in mice expressing the ACVR1 mutation associated with human fibrodysplasia ossificans progressiva. In cells migrating into BMP2 implants, DDR2 is co-expressed with GLI1, a skeletal stem cell marker, and DDR2/GLI1-positive cells participate in BMP2-induced bone formation where they contribute to chondrogenic and osteogenic lineages. Consistent with this distribution, conditional knockout of Ddr2 in Gli1-expressing cells inhibited bone formation to the same extent seen in globally Ddr2-deficient animals. This response was explained by selective inhibition of Gli1+ cell proliferation without changes in apoptosis. The basis for this DDR2 requirement was explored further using bone marrow stromal cells. Although Ddr2 deficiency inhibited BMP2-dependent chondrocyte and osteoblast differentiation and in vivo, bone formation, early BMP responses including SMAD phosphorylation remained largely intact. Instead, Ddr2 deficiency reduced the nuclear/cytoplasmic ratio of the Hippo pathway intermediates, YAP and TAZ. This suggests that DDR2 regulates Hippo pathway-mediated responses to the collagen matrix, which subsequently affect BMP responsiveness. In summary, DDR2 is an important modulator of BMP signaling and a potential therapeutic target both for enhancing regeneration and treating HO.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"375 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917137","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

Neuronal guidance factor Sema3A inhibits neurite ingrowth and prevents chondrocyte hypertrophy in the degeneration of knee cartilage in mice, monkeys and humans 在小鼠、猴子和人的膝关节软骨变性中，神经元引导因子Sema3A抑制神经突向内生长，防止软骨细胞肥大

IF 12.7 1区医学

Bone Research Pub Date : 2025-01-02 DOI: 10.1038/s41413-024-00382-0

Shishu Huang, Dashuang Gao, Zhenxia Li, Hongchen He, Xi Yu, Xuanhe You, Diwei Wu, Ze Du, Jiancheng Zeng, Xiaojun Shi, Qinshen Hu, Yong Nie, Zhong Zhang, Zeyu Luo, Duan Wang, Zhihe Zhao, Lingli Li, Guanglin Wang, Liping Wang, Zongke Zhou, Di Chen, Fan Yang

{"title":"Neuronal guidance factor Sema3A inhibits neurite ingrowth and prevents chondrocyte hypertrophy in the degeneration of knee cartilage in mice, monkeys and humans","authors":"Shishu Huang, Dashuang Gao, Zhenxia Li, Hongchen He, Xi Yu, Xuanhe You, Diwei Wu, Ze Du, Jiancheng Zeng, Xiaojun Shi, Qinshen Hu, Yong Nie, Zhong Zhang, Zeyu Luo, Duan Wang, Zhihe Zhao, Lingli Li, Guanglin Wang, Liping Wang, Zongke Zhou, Di Chen, Fan Yang","doi":"10.1038/s41413-024-00382-0","DOIUrl":"https://doi.org/10.1038/s41413-024-00382-0","url":null,"abstract":"Osteoarthritis (OA) is a degenerative joint disease accompanied with the loss of cartilage and consequent nociceptive symptoms. Normal articular cartilage maintains at aneural state. Neuron guidance factor Semaphorin 3A (Sema3A) is a membrane-associated secreted protein with chemorepulsive properties for axons. However, the role of Sema3A in articular cartilage is still not clear. In the present studies, we investigated the functions of Sema3A in OA development in mice, non-human primates, and patients with OA. Sema3A has a protective effect on cartilage degradation, validated by the organoid culture in vitro and confirmed in chondrocyte-specific Sema3A conditional knockout mice. We demonstrated that Sema3A is a key molecule in maintaining cartilage homeostasis from chondrocyte hypertrophy via activating the PI3K pathway. The potential usage of Sema3A for OA treatment was validated in mouse and Rhesus macaque OA models through intra-articular injection of Sema3A, and also in patients by administering Sema3A containing platelet-rich plasma into the knee joints. Our studies demonstrated that Sema3A exerts a critical role in inhibiting neurite ingrowth and preventing chondrocyte hypertrophy in cartilage, and could be potentially used for OA treatment.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"17 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911769","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

MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2 MYSM1通过招募PP2A去泛素化和去磷酸化RIPK2来减轻骨关节炎

IF 12.7 1区医学

Bone Research Pub Date : 2025-01-02 DOI: 10.1038/s41413-024-00368-y

Kang Wei, Chuankun Zhou, Zixing Shu, Xingru Shang, Yi Zou, Wei Zhou, Huanhuan Xu, Yulin Liang, Tian Ma, Xuying Sun, Jun Xiao

{"title":"MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2","authors":"Kang Wei, Chuankun Zhou, Zixing Shu, Xingru Shang, Yi Zou, Wei Zhou, Huanhuan Xu, Yulin Liang, Tian Ma, Xuying Sun, Jun Xiao","doi":"10.1038/s41413-024-00368-y","DOIUrl":"https://doi.org/10.1038/s41413-024-00368-y","url":null,"abstract":"Osteoarthritis (OA), the most prevalent degenerative joint disease, is marked by cartilage degradation and pathological alterations in surrounding tissues. Currently, no effective disease-modifying treatments exist. This study aimed to elucidate the critical roles of Myb-like, SWIRM, and MPN domains 1 (MYSM1) and its downstream effector, Receptor-interacting protein kinase 2 (RIPK2), in OA pathogenesis and the underlying mechanisms. Our findings revealed reduced MYSM1 levels in the cartilage of OA patients and mouse models. Genetic or adenovirus-induced MYSM1 knockout exacerbated OA progression in mice, whereas MYSM1 overexpression mitigated it. Mechanistically, MYSM1 inhibited the NF-κB and MAPK signaling pathways. Conversely, downstream RIPK2 significantly increased OA-like phenotypes and activated the NF-κB and MAPK pathways. The Ripk2S176D mutation accelerated OA pathogenesis, while Ripk2 silencing or Ripk2S176A mutation deactivated NF-κB and MAPK pathways, counteracting the role of MYSM1. MYSM1 deubiquitinates and dephosphorylates RIPK2S176 by recruiting protein phosphatase 2 A (PP2A). These results suggest that targeting MYSM1 or downstream RIPK2 offers promising therapeutic potential for OA.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"6 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911770","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

Pivotal roles of biglycan and decorin in regulating bone mass, water retention, and bone toughness 巨聚糖和装饰素在调节骨量、水潴留和骨韧性中的关键作用

IF 12.7 1区医学

Bone Research Pub Date : 2025-01-02 DOI: 10.1038/s41413-024-00380-2

Rui Hua, Yan Han, Qingwen Ni, Roberto J. Fajardo, Renato V. Iozzo, Rafay Ahmed, Jeffry S. Nyman, Xiaodu Wang, Jean X. Jiang

{"title":"Pivotal roles of biglycan and decorin in regulating bone mass, water retention, and bone toughness","authors":"Rui Hua, Yan Han, Qingwen Ni, Roberto J. Fajardo, Renato V. Iozzo, Rafay Ahmed, Jeffry S. Nyman, Xiaodu Wang, Jean X. Jiang","doi":"10.1038/s41413-024-00380-2","DOIUrl":"https://doi.org/10.1038/s41413-024-00380-2","url":null,"abstract":"Proteoglycans, key components of non-collagenous proteins in the bone matrix, attract water through their negatively charged glycosaminoglycan chains. Among these proteoglycans, biglycan (Bgn) and decorin (Dcn) are major subtypes, yet their distinct roles in bone remain largely elusive. In this study, we utilized single knockout (KO) mouse models and successfully generated double KO (dKO) models despite challenges with low yield. Bgn deficiency, but not Dcn deficiency, decreased trabecular bone mass, with more pronounced bone loss in dKO mice. Low-field nuclear magnetic resonance measurements showed a marked decrease in bound water among all KO groups, especially in Bgn KO and dKO mice. Moreover, both Bgn KO and dKO mice exhibited reduced fracture toughness compared to Dcn KO mice. Dcn was significantly upregulated in Bgn KO mice, while a modest upregulation of Bgn was observed in Dcn KO mice, indicating Bgn’s predominant role in bone. High resolution atomic force microscopy showed decreased in situ permanent energy dissipation and increased elastic modulus in the extrafibrillar matrix of Bgn/Dcn deficient mice, which were diminished upon dehydration. Furthermore, we found that both Bgn and Dcn are indispensable for the activation of ERK and p38 MAPK signaling pathways. Collectively, our results highlight the distinct and indispensable roles of Bgn and Dcn in maintaining bone structure, water retention, and bulk/in situ tissue properties in the bone matrix, with Bgn exerting a predominant influence.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"68 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911772","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

Cellular and molecular mechanisms underlying obesity in degenerative spine and joint diseases 退行性脊柱和关节疾病中肥胖的细胞和分子机制

IF 12.7 1区医学

Bone Research Pub Date : 2024-12-11 DOI: 10.1038/s41413-024-00388-8

Qian Xiang, Zhenquan Wu, Yongzhao Zhao, Shuo Tian, Jialiang Lin, Longjie Wang, Shuai Jiang, Zhuoran Sun, Weishi Li

{"title":"Cellular and molecular mechanisms underlying obesity in degenerative spine and joint diseases","authors":"Qian Xiang, Zhenquan Wu, Yongzhao Zhao, Shuo Tian, Jialiang Lin, Longjie Wang, Shuai Jiang, Zhuoran Sun, Weishi Li","doi":"10.1038/s41413-024-00388-8","DOIUrl":"https://doi.org/10.1038/s41413-024-00388-8","url":null,"abstract":"Degenerative spine and joint diseases, including intervertebral disc degeneration (IDD), ossification of the spinal ligaments (OSL), and osteoarthritis (OA), are common musculoskeletal diseases that cause pain or disability to the patients. However, the pathogenesis of these musculoskeletal disorders is complex and has not been elucidated clearly to date. As a matter of fact, the spine and joints are not independent of other organs and tissues. Recently, accumulating evidence demonstrates the association between obesity and degenerative musculoskeletal diseases. Obesity is a common metabolic disease characterized by excessive adipose tissue or abnormal adipose distribution in the body. Excessive mechanical stress is regarded as a critical risk factor for obesity-related pathology. Additionally, obesity-related factors, mainly including lipid metabolism disorder, dysregulated pro-inflammatory adipokines and cytokines, are reported as plausible links between obesity and various human diseases. Importantly, these obesity-related factors are deeply involved in the regulation of cell phenotypes and cell fates, extracellular matrix (ECM) metabolism, and inflammation in the pathophysiological processes of degenerative spine and joint diseases. In this study, we systematically discuss the potential cellular and molecular mechanisms underlying obesity in these degenerative musculoskeletal diseases, and hope to provide novel insights for developing targeted therapeutic strategies.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"77 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804795","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 osteogenic potential of iPSC-derived mesenchymal progenitor cells following genome editing of GWAS variants in the RUNX1 gene RUNX1基因GWAS变异基因组编辑后ipsc衍生间充质祖细胞成骨潜能增强

IF 12.7 1区医学

Bone Research Pub Date : 2024-12-06 DOI: 10.1038/s41413-024-00369-x

Nazir M. Khan, Andrea Wilderman, Jarred M. Kaiser, Archana Kamalakar, Steven L. Goudy, Justin Cotney, Hicham Drissi

{"title":"Enhanced osteogenic potential of iPSC-derived mesenchymal progenitor cells following genome editing of GWAS variants in the RUNX1 gene","authors":"Nazir M. Khan, Andrea Wilderman, Jarred M. Kaiser, Archana Kamalakar, Steven L. Goudy, Justin Cotney, Hicham Drissi","doi":"10.1038/s41413-024-00369-x","DOIUrl":"https://doi.org/10.1038/s41413-024-00369-x","url":null,"abstract":"Recent genome-wide association studies (GWAS) identified 518 significant loci associated with bone mineral density (BMD), including variants at the RUNX1 locus (rs13046645, rs2834676, and rs2834694). However, their regulatory impact on RUNX1 expression and bone formation remained unclear. This study utilized human induced pluripotent stem cells (iPSCs) differentiated into osteoblasts to investigate these variants’ regulatory roles. CRISPR/Cas9 was employed to generate mutant (Δ) iPSC lines lacking these loci at the RUNX1 locus. Deletion lines (Δ1 and Δ2) were created in iPSCs to assess the effects of removing regions containing these loci. Deletion lines exhibited enhanced osteogenic potential, with increased expression of osteogenic marker genes and Alizarin Red staining. Circularized chromosome conformation capture (4C-Seq) was utilized to analyze interactions between BMD-associated loci and the RUNX1 promoter during osteogenesis. Analysis revealed altered chromatin interactions with multiple gene promoters including RUNX1 isoform, as well as SETD4, a histone methyltransferase, indicating their regulatory influence. Interestingly, both deletion lines notably stimulated the expression of the long isoform of RUNX1, with more modest effects on the shorter isoform. Consistent upregulation of SETD4 and other predicted targets within the Δ2 deletion suggested its removal removed a regulatory hub constraining expression of multiple genes at this locus. In vivo experiments using a bone defect model in mice demonstrated increased bone regeneration with homozygous deletion of the Δ2 region. These findings indicate that BMD-associated variants within the RUNX1 locus regulate multiple effector genes involved in osteoblast commitment, providing valuable insights into genetic regulation of bone density and potential therapeutic targets.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"216 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783297","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

Cross-talk of inflammation and cellular senescence: a new insight into the occurrence and progression of osteoarthritis 炎症和细胞衰老的相互作用：对骨关节炎发生和发展的新认识

IF 12.7 1区医学

Bone Research Pub Date : 2024-12-03 DOI: 10.1038/s41413-024-00375-z

Zeyu Han, Ketao Wang, Shenglong Ding, Mingzhu Zhang

{"title":"Cross-talk of inflammation and cellular senescence: a new insight into the occurrence and progression of osteoarthritis","authors":"Zeyu Han, Ketao Wang, Shenglong Ding, Mingzhu Zhang","doi":"10.1038/s41413-024-00375-z","DOIUrl":"https://doi.org/10.1038/s41413-024-00375-z","url":null,"abstract":"Osteoarthritis (OA) poses a significant challenge in orthopedics. Inflammatory pathways are regarded as central mechanisms in the onset and progression of OA. Growing evidence suggests that senescence acts as a mediator in inflammation-induced OA. Given the lack of effective treatments for OA, there is an urgent need for a clearer understanding of its pathogenesis. In this review, we systematically summarize the cross-talk between cellular senescence and inflammation in OA. We begin by focusing on the mechanisms and hallmarks of cellular senescence, summarizing evidence that supports the relationship between cellular senescence and inflammation. We then discuss the mechanisms of interaction between cellular senescence and inflammation, including senescence-associated secretory phenotypes (SASP) and the effects of pro- and anti-inflammatory interventions on cellular senescence. Additionally, we focus on various types of cellular senescence in OA, including senescence in cartilage, subchondral bone, synovium, infrapatellar fat pad, stem cells, and immune cells, elucidating their mechanisms and impacts on OA. Finally, we highlight the potential of therapies targeting senescent cells in OA as a strategy for promoting cartilage regeneration.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"80 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759987","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

DNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosis DNMT畸变引起的GPX4抑制可促进成骨细胞铁下垂和骨质疏松

IF 12.7 1区医学

Bone Research Pub Date : 2024-12-02 DOI: 10.1038/s41413-024-00365-1

Binjia Ruan, Jian Dong, Fanhao Wei, Zhiqiang Huang, Bin Yang, Lijun Zhang, Chuling Li, Hui Dong, Wangsen Cao, Hongwei Wang, Yongxiang Wang

{"title":"DNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosis","authors":"Binjia Ruan, Jian Dong, Fanhao Wei, Zhiqiang Huang, Bin Yang, Lijun Zhang, Chuling Li, Hui Dong, Wangsen Cao, Hongwei Wang, Yongxiang Wang","doi":"10.1038/s41413-024-00365-1","DOIUrl":"https://doi.org/10.1038/s41413-024-00365-1","url":null,"abstract":"Osteoporosis (OP) is a common and fracture-prone skeletal disease characterized by deteriorated trabecular microstructure and pathologically involving various forms of regulated bone cell death. However, the exact role, cellular nature and regulatory mechanisms of ferroptosis in OP are not fully understood. Here, we reported that OP femurs from ovariectomized (Ovx) mice exhibited pronounced iron deposition, ferroptosis, and transcriptional suppression of a key anti-ferroptotic factor GPX4 (glutathione peroxidase 4). GPX4 suppression was accompanied by hypermethylation of the Gpx4 promoter and an increase in DNA methyltransferases DNMT1/3a/3b and was transcriptionally promoted by repressive KLF5 and the transcriptional corepressors NCoR and SnoN. Conversely, DNMT inhibition with SGI-1027 reversed promoter hypermethylation, GPX4 suppression and ferroptotic osteoporosis. In cultured primary bone cells, ferric ammonium citrate (FAC) mimicking iron loading similarly induced GPX4 suppression and ferroptosis in osteoblasts but not in osteoclasts, which were rescued by siRNA-mediated individual knockdown of DNMT 1/3a/3b. Intriguingly, SGI-1027 alleviated the ferroptotic changes caused by FAC, but not by a GPX4 inactivator RSL3. More importantly, we generated a strain of osteoblast-specific Gpx4 haplo-deficient mice Gpx4Ob+/− that developed spontaneous and more severe ferroptotic OP alterations after Ovx operation, and showed that GPX4 inactivation by RSL3 or semi-knockout in osteoblasts largely abolished the anti-ferroptotic and osteoprotective effects of SGI-1027. Taken together, our data suggest that GPX4 epigenetic suppression caused by DNMT aberration and the resulting osteoblastic ferroptosis contribute significantly to OP pathogenesis, and that the strategies preserving GPX4 by DNMT intervention are potentially effective to treat OP and related bone disorders.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"27 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758494","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

KMT2A regulates the autophagy-GATA4 axis through METTL3-mediated m6A modification of ATG4a to promote NPCs senescence and IVDD progression KMT2A 通过 METTL3 介导的 ATG4a m6A 修饰调节自噬-GATA4 轴，从而促进鼻咽癌的衰老和 IVDD 的进展

IF 12.7 1区医学

Bone Research Pub Date : 2024-11-21 DOI: 10.1038/s41413-024-00373-1

Ouqiang Wu, Yuxin Jin, Zhiguang Zhang, Hao Zhou, Wenbin Xu, Linjie Chen, Morgan Jones, Kenny Yat Hong Kwan, Jianyuan Gao, Kai Zhang, Xiaofei Cheng, Qizhu Chen, Xinzhou Wang, Yan Michael Li, Zhenyu Guo, Jing Sun, Zhihua Chen, Bin Wang, Xiangyang Wang, Shuying Shen, Aimin Wu

{"title":"KMT2A regulates the autophagy-GATA4 axis through METTL3-mediated m6A modification of ATG4a to promote NPCs senescence and IVDD progression","authors":"Ouqiang Wu, Yuxin Jin, Zhiguang Zhang, Hao Zhou, Wenbin Xu, Linjie Chen, Morgan Jones, Kenny Yat Hong Kwan, Jianyuan Gao, Kai Zhang, Xiaofei Cheng, Qizhu Chen, Xinzhou Wang, Yan Michael Li, Zhenyu Guo, Jing Sun, Zhihua Chen, Bin Wang, Xiangyang Wang, Shuying Shen, Aimin Wu","doi":"10.1038/s41413-024-00373-1","DOIUrl":"https://doi.org/10.1038/s41413-024-00373-1","url":null,"abstract":"Intervertebral disc degeneration (IVDD), a disease associated with ageing, is characterised by a notable increase in senescent nucleus pulposus cells (NPCs) as IVDD progresses. However, the specific mechanisms that regulate the senescence of NPCs remain unknown. In this study, we observed impaired autophagy in IVDD-NPCs, which contributed to the upregulation of NPCs senescence and the senescence-associated secretory phenotype (SASP). The dysregulated SASP disrupted NPCs viability and initiated extracellular matrix degradation. Conversely, the restoration of autophagy reversed the senescence phenotype by inhibiting GATA binding protein 4 (GATA4). Moreover, we made the novel observation that a cross-talk between histone H3 lysine 4 trimethylation (H3K4me3) modification and N6-methyladenosine(m6A)-methylated modification regulates autophagy in IVDD-NPCs. Mechanistically, lysine methyltransferase 2A (KMT2A) promoted the expression of methyltransferase-like 3 (METTL3) through H3K4me3 modification, whereas METTL3-mediated m6A modification reduced the expression of autophagy-associated 4a (ATG4a) by attenuating its RNA stability, leading to autophagy damage in NPCs. Silencing KMT2A and METTL3 enhanced autophagic flux and suppressed SASP expression in IVDD-NPCs. Therefore, targeting the H3K4me3-regulated METTL3/ATG4a/GATA4 axis may represent a promising new therapeutic strategy for IVDD.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"33 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678169","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

Engineering bone/cartilage organoids: strategy, progress, and application 骨/软骨有机体工程：战略、进展与应用

IF 12.7 1区医学

Bone Research Pub Date : 2024-11-20 DOI: 10.1038/s41413-024-00376-y

Long Bai, Dongyang Zhou, Guangfeng Li, Jinlong Liu, Xiao Chen, Jiacan Su

{"title":"Engineering bone/cartilage organoids: strategy, progress, and application","authors":"Long Bai, Dongyang Zhou, Guangfeng Li, Jinlong Liu, Xiao Chen, Jiacan Su","doi":"10.1038/s41413-024-00376-y","DOIUrl":"https://doi.org/10.1038/s41413-024-00376-y","url":null,"abstract":"The concept and development of bone/cartilage organoids are rapidly gaining momentum, providing opportunities for both fundamental and translational research in bone biology. Bone/cartilage organoids, essentially miniature bone/cartilage tissues grown in vitro, enable the study of complex cellular interactions, biological processes, and disease pathology in a representative and controlled environment. This review provides a comprehensive and up-to-date overview of the field, focusing on the strategies for bone/cartilage organoid construction strategies, progresses in the research, and potential applications. We delve into the significance of selecting appropriate cells, matrix gels, cytokines/inducers, and construction techniques. Moreover, we explore the role of bone/cartilage organoids in advancing our understanding of bone/cartilage reconstruction, disease modeling, drug screening, disease prevention, and treatment strategies. While acknowledging the potential of these organoids, we discuss the inherent challenges and limitations in the field and propose potential solutions, including the use of bioprinting for organoid induction, AI for improved screening processes, and the exploration of assembloids for more complex, multicellular bone/cartilage organoids models. We believe that with continuous refinement and standardization, bone/cartilage organoids can profoundly impact patient-specific therapeutic interventions and lead the way in regenerative medicine.<figure></figure>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"99 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673906","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