Bone Research最新文献

Tree shrew as a new animal model for musculoskeletal disorders and aging

IF 12.7 1区医学

Bone Research Pub Date : 2025-01-02 DOI: 10.1038/s41413-024-00367-z

Xiaocui Wei, Honghao Li, Jingyang Qiu, Jianlin Jiao, Xiongtian Guo, Gaosheng Yin, Ping Yang, Yi Han, Qiongzhi Zhao, Hao Zeng, Zhi Rao, Xuefei Gao, Kai Li, Pinglin Lai, Sheng Zhang, Chengliang Yang, Di Lu, Xiaochun Bai

{"title":"Tree shrew as a new animal model for musculoskeletal disorders and aging","authors":"Xiaocui Wei, Honghao Li, Jingyang Qiu, Jianlin Jiao, Xiongtian Guo, Gaosheng Yin, Ping Yang, Yi Han, Qiongzhi Zhao, Hao Zeng, Zhi Rao, Xuefei Gao, Kai Li, Pinglin Lai, Sheng Zhang, Chengliang Yang, Di Lu, Xiaochun Bai","doi":"10.1038/s41413-024-00367-z","DOIUrl":"https://doi.org/10.1038/s41413-024-00367-z","url":null,"abstract":"Intervertebral disc degeneration (IDD), osteoarthritis (OA), and osteoporosis (OP) are common musculoskeletal disorders (MSDs) with similar age-related risk factors, representing the leading causes of disability. However, successful therapeutic development and translation have been hampered by the lack of clinically-relevant animal models. In this study, we investigated the potential suitability of the tree shrew, a small mammal with a close genetic relationship to primates, as a new animal model for MSDs. Age-related spontaneous IDD in parallel with a gradual disappearance of notochordal cells were commonly observed in tree shrews upon skeletal maturity with no sex differences, while age-related osteoporotic changes including bone loss in the metaphyses were primarily presented in aged females, similar to observations in humans. Moreover, in the osteochondral defect model, tree shrew cartilage exhibited behavior similar to that of humans, characterized by a more restricted self-healing capacity compared to the rapid spontaneous healing of joint surfaces observed in rats. The induced OA model in tree shrews was highly efficient and reproducible, characterized by gradual deterioration of articular cartilage, recapitulating the human OA phenotype to some degree. Surgery-induced IDD models were successfully established in tree shrews, in which the lumbar spine instability model developed slow progressive disc degeneration with more similarity to the clinical state, whereas the needle puncture model led to the rapid development of IDD with more severe symptoms. Taken together, our findings pave the way for the development of the tree shrew as a new animal model for the study of MSDs and aging.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"11 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917136","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 interoception and prospective application in biomaterials for bone regeneration

IF 12.7 1区医学

Bone Research Pub Date : 2025-01-02 DOI: 10.1038/s41413-024-00378-w

Long Bai, Jilong Li, Guangfeng Li, Dongyang Zhou, Jiacan Su, Changsheng Liu

{"title":"Skeletal interoception and prospective application in biomaterials for bone regeneration","authors":"Long Bai, Jilong Li, Guangfeng Li, Dongyang Zhou, Jiacan Su, Changsheng Liu","doi":"10.1038/s41413-024-00378-w","DOIUrl":"https://doi.org/10.1038/s41413-024-00378-w","url":null,"abstract":"Accumulating research has shed light on the significance of skeletal interoception, in maintaining physiological and metabolic homeostasis related to bone health. This review provides a comprehensive analysis of how skeletal interoception influences bone homeostasis, delving into the complex interplay between the nervous system and skeletal system. One key focus of the review is the role of various factors such as prostaglandin E2 (PGE2) in skeletal health via skeletal interoception. It explores how nerves innervating the bone tissue communicate with the central nervous system to regulate bone remodeling, a process critical for maintaining bone strength and integrity. Additionally, the review highlights the advancements in biomaterials designed to utilize skeletal interoception for enhancing bone regeneration and treatment of bone disorders. These biomaterials, tailored to interact with the body’s interoceptive pathways, are positioned at the forefront of innovative treatments for conditions like osteoporosis and fractures. They represent a convergence of bioengineering, neuroscience, and orthopedics, aiming to create more efficient and targeted therapies for bone-related disorders. In conclusion, the review underscores the importance of skeletal interoception in physiological regulation and its potential in developing more effective therapies for bone regeneration. It emphasizes the need for further research to fully understand the mechanisms of skeletal interoception and to harness its therapeutic potential fully.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"32 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911771","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

Discoidin domain receptor 2 is an important modulator of BMP signaling during heterotopic bone formation

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

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

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

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

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

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

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

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