首页 > 最新文献

Bone Research最新文献

英文 中文
Combining single-cell RNA sequencing and population-based studies reveals hand osteoarthritis-associated chondrocyte subpopulations and pathways. 单细胞RNA测序和基于人群的研究相结合揭示了手部骨关节炎相关软骨细胞亚群和途径。
IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2023-11-02 DOI: 10.1038/s41413-023-00292-7
Hui Li, Xiaofeng Jiang, Yongbing Xiao, Yuqing Zhang, Weiya Zhang, Michael Doherty, Jacquelyn Nestor, Changjun Li, Jing Ye, Tingting Sha, Houchen Lyu, Jie Wei, Chao Zeng, Guanghua Lei

Hand osteoarthritis is a common heterogeneous joint disorder with unclear molecular mechanisms and no disease-modifying drugs. In this study, we performed single-cell RNA sequencing analysis to compare the cellular composition and subpopulation-specific gene expression between cartilage with macroscopically confirmed osteoarthritis (n = 5) and cartilage without osteoarthritis (n = 5) from the interphalangeal joints of five donors. Of 105 142 cells, we identified 13 subpopulations, including a novel subpopulation with inflammation-modulating potential annotated as inflammatory chondrocytes. Fibrocartilage chondrocytes exhibited extensive alteration of gene expression patterns in osteoarthritic cartilage compared with nonosteoarthritic cartilage. Both inflammatory chondrocytes and fibrocartilage chondrocytes showed a trend toward increased numbers in osteoarthritic cartilage. In these two subpopulations from osteoarthritic cartilage, the ferroptosis pathway was enriched, and expression of iron overload-related genes, e.g., FTH1, was elevated. To verify these findings, we conducted a Mendelian randomization study using UK Biobank and a population-based cross-sectional study using data collected from Xiangya Osteoarthritis Study. Genetic predisposition toward higher expression of FTH1 mRNA significantly increased the risk of hand osteoarthritis (odds ratio = 1.07, 95% confidence interval: 1.02-1.11) among participants (n = 332 668) in UK Biobank. High levels of serum ferritin (encoded by FTH1), a biomarker of body iron overload, were significantly associated with a high prevalence of hand osteoarthritis among participants (n = 1 241) of Xiangya Osteoarthritis Study (P-for-trend = 0.037). In conclusion, our findings indicate that inflammatory and fibrocartilage chondrocytes are key subpopulations and that ferroptosis may be a key pathway in hand osteoarthritis, providing new insights into the pathophysiology and potential therapeutic targets of hand osteoarthritis.

手骨关节炎是一种常见的异质性关节疾病,其分子机制尚不清楚,也没有治疗疾病的药物。在这项研究中,我们进行了单细胞RNA测序分析,以比较宏观证实的骨关节炎软骨(n = 5) 无骨关节炎的软骨(n = 5) 来自五个供体的指间关节。共105个 142个细胞,我们鉴定了13个亚群,包括一个具有炎症调节潜力的新亚群,注释为炎症软骨细胞。与非骨性关节炎软骨相比,纤维软骨细胞在骨关节炎软骨中表现出广泛的基因表达模式改变。炎性软骨细胞和纤维软骨细胞在骨关节炎软骨中都显示出数量增加的趋势。在这两个来自骨关节炎软骨的亚群中,脱铁途径富集,铁过载相关基因(如FTH1)的表达升高。为了验证这些发现,我们使用英国生物库进行了一项孟德尔随机化研究,并使用湘雅骨关节炎研究收集的数据进行了一次基于人群的横断面研究。FTH1 mRNA高表达的遗传倾向显著增加了患手部骨关节炎的风险(比值比 = 1.07,95%置信区间:1.02-1.11) = 332 668)在英国生物银行。高水平的血清铁蛋白(由FTH1编码)是身体铁过载的生物标志物,与参与者中手部骨关节炎的高患病率显著相关(n = 1. 241)的湘雅骨关节炎研究(P为趋势 = 0.037)。总之,我们的研究结果表明,炎性软骨细胞和纤维软骨软骨细胞是关键的亚群,脱铁症可能是手部骨关节炎的关键途径,为手部骨骨头炎的病理生理学和潜在的治疗靶点提供了新的见解。
{"title":"Combining single-cell RNA sequencing and population-based studies reveals hand osteoarthritis-associated chondrocyte subpopulations and pathways.","authors":"Hui Li, Xiaofeng Jiang, Yongbing Xiao, Yuqing Zhang, Weiya Zhang, Michael Doherty, Jacquelyn Nestor, Changjun Li, Jing Ye, Tingting Sha, Houchen Lyu, Jie Wei, Chao Zeng, Guanghua Lei","doi":"10.1038/s41413-023-00292-7","DOIUrl":"10.1038/s41413-023-00292-7","url":null,"abstract":"<p><p>Hand osteoarthritis is a common heterogeneous joint disorder with unclear molecular mechanisms and no disease-modifying drugs. In this study, we performed single-cell RNA sequencing analysis to compare the cellular composition and subpopulation-specific gene expression between cartilage with macroscopically confirmed osteoarthritis (n = 5) and cartilage without osteoarthritis (n = 5) from the interphalangeal joints of five donors. Of 105 142 cells, we identified 13 subpopulations, including a novel subpopulation with inflammation-modulating potential annotated as inflammatory chondrocytes. Fibrocartilage chondrocytes exhibited extensive alteration of gene expression patterns in osteoarthritic cartilage compared with nonosteoarthritic cartilage. Both inflammatory chondrocytes and fibrocartilage chondrocytes showed a trend toward increased numbers in osteoarthritic cartilage. In these two subpopulations from osteoarthritic cartilage, the ferroptosis pathway was enriched, and expression of iron overload-related genes, e.g., FTH1, was elevated. To verify these findings, we conducted a Mendelian randomization study using UK Biobank and a population-based cross-sectional study using data collected from Xiangya Osteoarthritis Study. Genetic predisposition toward higher expression of FTH1 mRNA significantly increased the risk of hand osteoarthritis (odds ratio = 1.07, 95% confidence interval: 1.02-1.11) among participants (n = 332 668) in UK Biobank. High levels of serum ferritin (encoded by FTH1), a biomarker of body iron overload, were significantly associated with a high prevalence of hand osteoarthritis among participants (n = 1 241) of Xiangya Osteoarthritis Study (P-for-trend = 0.037). In conclusion, our findings indicate that inflammatory and fibrocartilage chondrocytes are key subpopulations and that ferroptosis may be a key pathway in hand osteoarthritis, providing new insights into the pathophysiology and potential therapeutic targets of hand osteoarthritis.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":14.3,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10620170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71429609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Glycobiology in osteoclast differentiation and function. 破骨细胞分化和功能中的糖生物学。
1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-26 DOI: 10.1038/s41413-023-00293-6
Shufa Yang, Ziyi He, Tuo Wu, Shunlei Wang, Hui Dai

Glycans, either alone or in complex with glycan-binding proteins, are essential structures that can regulate cell biology by mediating protein stability or receptor dimerization under physiological and pathological conditions. Certain glycans are ligands for lectins, which are carbohydrate-specific receptors. Bone is a complex tissue that provides mechanical support for muscles and joints, and the regulation of bone mass in mammals is governed by complex interplay between bone-forming cells, called osteoblasts, and bone-resorbing cells, called osteoclasts. Bone erosion occurs when bone resorption notably exceeds bone formation. Osteoclasts may be activated during cancer, leading to a range of symptoms, including bone pain, fracture, and spinal cord compression. Our understanding of the role of protein glycosylation in cells and tissues involved in osteoclastogenesis suggests that glycosylation-based treatments can be used in the management of diseases. The aims of this review are to clarify the process of bone resorption and investigate the signaling pathways mediated by glycosylation and their roles in osteoclast biology. Moreover, we aim to outline how the lessons learned about these approaches are paving the way for future glycobiology-focused therapeutics.

聚糖,无论是单独的还是与聚糖结合蛋白复合的,都是在生理和病理条件下可以通过介导蛋白质稳定性或受体二聚化来调节细胞生物学的基本结构。某些聚糖是凝集素的配体,凝集素是碳水化合物特异性受体。骨是一种为肌肉和关节提供机械支撑的复杂组织,哺乳动物对骨量的调节由称为成骨细胞的成骨细胞和称为破骨细胞的骨吸收细胞之间的复杂相互作用决定。当骨吸收明显超过骨形成时,就会发生骨侵蚀。在癌症期间,破骨细胞可能被激活,导致一系列症状,包括骨痛、骨折和脊髓压迫。我们对蛋白质糖基化在参与破骨细胞生成的细胞和组织中的作用的理解表明,基于糖基化的治疗可以用于疾病的管理。这篇综述的目的是阐明骨吸收的过程,并研究糖基化介导的信号通路及其在破骨细胞生物学中的作用。此外,我们的目标是概述这些方法的经验教训如何为未来以糖生物学为重点的治疗方法铺平道路。
{"title":"Glycobiology in osteoclast differentiation and function.","authors":"Shufa Yang, Ziyi He, Tuo Wu, Shunlei Wang, Hui Dai","doi":"10.1038/s41413-023-00293-6","DOIUrl":"10.1038/s41413-023-00293-6","url":null,"abstract":"<p><p>Glycans, either alone or in complex with glycan-binding proteins, are essential structures that can regulate cell biology by mediating protein stability or receptor dimerization under physiological and pathological conditions. Certain glycans are ligands for lectins, which are carbohydrate-specific receptors. Bone is a complex tissue that provides mechanical support for muscles and joints, and the regulation of bone mass in mammals is governed by complex interplay between bone-forming cells, called osteoblasts, and bone-resorbing cells, called osteoclasts. Bone erosion occurs when bone resorption notably exceeds bone formation. Osteoclasts may be activated during cancer, leading to a range of symptoms, including bone pain, fracture, and spinal cord compression. Our understanding of the role of protein glycosylation in cells and tissues involved in osteoclastogenesis suggests that glycosylation-based treatments can be used in the management of diseases. The aims of this review are to clarify the process of bone resorption and investigate the signaling pathways mediated by glycosylation and their roles in osteoclast biology. Moreover, we aim to outline how the lessons learned about these approaches are paving the way for future glycobiology-focused therapeutics.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54232457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genetic interactions between polycystin-1 and Wwtr1 in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice. 成骨细胞中polycystin-1和Wwtr1之间的遗传相互作用确定了一种新的调节小鼠骨形成的机械传感机制。
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-26 DOI: 10.1038/s41413-023-00295-4
Zhousheng Xiao, Li Cao, Micholas Dean Smith, Hanxuan Li, Wei Li, Jeremy C Smith, Leigh Darryl Quarles

Molecular mechanisms transducing physical forces in the bone microenvironment to regulate bone mass are poorly understood. Here, we used mouse genetics, mechanical loading, and pharmacological approaches to test the possibility that polycystin-1 and Wwtr1 have interdependent mechanosensing functions in osteoblasts. We created and compared the skeletal phenotypes of control Pkd1flox/+;Wwtr1flox/+, Pkd1Oc-cKO, Wwtr1Oc-cKO, and Pkd1/Wwtr1Oc-cKO mice to investigate genetic interactions. Consistent with an interaction between polycystins and Wwtr1 in bone in vivo, Pkd1/Wwtr1Oc-cKO mice exhibited greater reductions of BMD and periosteal MAR than either Wwtr1Oc-cKO or Pkd1Oc-cKO mice. Micro-CT 3D image analysis indicated that the reduction in bone mass was due to greater loss in both trabecular bone volume and cortical bone thickness in Pkd1/Wwtr1Oc-cKO mice compared to either Pkd1Oc-cKO or Wwtr1Oc-cKO mice. Pkd1/Wwtr1Oc-cKO mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to Pkd1Oc-cKO or Wwtr1Oc-cKO mice. Moreover, we found that Pkd1/Wwtr1Oc-cKO mice exhibited impaired responses to tibia mechanical loading in vivo and attenuation of load-induced mechanosensing gene expression compared to control mice. Finally, control mice treated with a small molecule mechanomimetic, MS2 that activates the polycystin complex resulted in marked increases in femoral BMD and periosteal MAR compared to vehicle control. In contrast, Pkd1/Wwtr1Oc-cKO mice were resistant to the anabolic effects of MS2. These findings suggest that PC1 and Wwtr1 form an anabolic mechanotransduction signaling complex that mediates mechanical loading responses and serves as a potential novel therapeutic target for treating osteoporosis.

在骨微环境中传递物理力以调节骨量的分子机制尚不清楚。在这里,我们使用小鼠遗传学、机械负荷和药理学方法来测试多囊蛋白-1和Wwtr1在成骨细胞中具有相互依赖的机械传感功能的可能性。我们创建并比较了对照Pkd1flox/+的骨骼表型;Wwtr1flox/+、Pkd1Oc cKO、Wwtr1Oc cKO和Pkd1/Wwtr1Oc-cKO小鼠,以研究遗传相互作用。与体内骨中微囊藻毒素和Wwtr1之间的相互作用一致,Pkd1/Wwtr1Oc-cKO小鼠比Wwtr1Oc-cKO或Pkd1Oc-cKO小鼠表现出更大的BMD和骨膜MAR降低。Micro-CT 3D图像分析表明,与Pkd1Oc cKO或Wwtr1Oc cKO小鼠相比,Pkd1/Wwtr1Oc-cKO小鼠的骨量减少是由于小梁骨体积和皮质骨厚度的损失更大。与Pkd1Oc cKO或Wwtr1Oc cKO小鼠相比,Pkd1/Wwtr1Oc-cKO小鼠在骨中的机械感应和成骨基因表达谱也显示出加性降低。此外,我们发现,与对照小鼠相比,Pkd1/Wwtr1Oc-cKO小鼠在体内对胫骨机械负荷的反应受损,负荷诱导的机械感应基因表达减弱。最后,与载体对照相比,用激活polycystin复合物的小分子机械模拟物MS2处理的对照小鼠导致股骨BMD和骨膜MAR显著增加。相反,Pkd1/Wwtr1Oc-cKO小鼠对MS2的合成代谢作用具有抗性。这些发现表明PC1和Wwtr1形成合成代谢机械转导信号复合体,介导机械负荷反应,并作为治疗骨质疏松症的潜在新治疗靶点。
{"title":"Genetic interactions between polycystin-1 and Wwtr1 in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice.","authors":"Zhousheng Xiao, Li Cao, Micholas Dean Smith, Hanxuan Li, Wei Li, Jeremy C Smith, Leigh Darryl Quarles","doi":"10.1038/s41413-023-00295-4","DOIUrl":"10.1038/s41413-023-00295-4","url":null,"abstract":"<p><p>Molecular mechanisms transducing physical forces in the bone microenvironment to regulate bone mass are poorly understood. Here, we used mouse genetics, mechanical loading, and pharmacological approaches to test the possibility that polycystin-1 and Wwtr1 have interdependent mechanosensing functions in osteoblasts. We created and compared the skeletal phenotypes of control Pkd1<sup>flox/+</sup>;Wwtr1<sup>flox/+</sup>, Pkd1<sup>Oc-cKO</sup>, Wwtr1<sup>Oc-cKO</sup>, and Pkd1/Wwtr1<sup>Oc-cKO</sup> mice to investigate genetic interactions. Consistent with an interaction between polycystins and Wwtr1 in bone in vivo, Pkd1/Wwtr1<sup>Oc-cKO</sup> mice exhibited greater reductions of BMD and periosteal MAR than either Wwtr1<sup>Oc-cKO</sup> or Pkd1<sup>Oc-cKO</sup> mice. Micro-CT 3D image analysis indicated that the reduction in bone mass was due to greater loss in both trabecular bone volume and cortical bone thickness in Pkd1/Wwtr1<sup>Oc-cKO</sup> mice compared to either Pkd1<sup>Oc-cKO</sup> or Wwtr1<sup>Oc-cKO</sup> mice. Pkd1/Wwtr1<sup>Oc-cKO</sup> mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to Pkd1<sup>Oc-cKO</sup> or Wwtr1<sup>Oc-cKO</sup> mice. Moreover, we found that Pkd1/Wwtr1<sup>Oc-cKO</sup> mice exhibited impaired responses to tibia mechanical loading in vivo and attenuation of load-induced mechanosensing gene expression compared to control mice. Finally, control mice treated with a small molecule mechanomimetic, MS2 that activates the polycystin complex resulted in marked increases in femoral BMD and periosteal MAR compared to vehicle control. In contrast, Pkd1/Wwtr1<sup>Oc-cKO</sup> mice were resistant to the anabolic effects of MS2. These findings suggest that PC1 and Wwtr1 form an anabolic mechanotransduction signaling complex that mediates mechanical loading responses and serves as a potential novel therapeutic target for treating osteoporosis.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54232456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling. Trim21耗竭通过激活YAP1/β-catenin信号传导减轻骨质疏松症患者的骨丢失。
1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-26 DOI: 10.1038/s41413-023-00296-3
Ri-Xu Liu, Rong-He Gu, Zhi-Peng Li, Zhi-Quan Hao, Qin-Xiao Hu, Zhen-Yan Li, Xiao-Gang Wang, Wang Tang, Xiao-He Wang, Yu-Kai Zeng, Zhen-Wei Li, Qiu Dong, Xiao-Feng Zhu, Di Chen, Ke-Wei Zhao, Rong-Hua Zhang, Zhen-Gang Zha, Huan-Tian Zhang

Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21-/-) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21-/- and Ctsk-cre; Trim21f/f mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.

尽管含有三重基序(Trim)的蛋白质在自噬、先天免疫反应和细胞分化的调节中发挥着不同的作用,但它们在骨骼疾病中的作用在很大程度上是未知的。我们最近证明了Trim21在骨肉瘤中调节成骨细胞(OB)分化中起着至关重要的作用。然而,Trim21是如何导致包括骨质疏松症在内的骨骼退行性疾病的,目前尚不清楚。首先,对人和小鼠的骨标本进行了评估,结果显示,从骨质疏松症患者获得的骨组织中,Trim21的表达显著升高。接下来,我们发现,与同窝对照相比,Trim21基因(KO,Trim21-/-)的整体敲除会导致更高的骨量。我们进一步证明,Trim21的缺失通过增强骨髓间充质干细胞(BMSCs)的成骨分化和提高OBs的活性来促进骨形成;此外,Trim21耗竭抑制了RAW264.7细胞的破骨细胞(OC)形成。此外,OCs与从Trim21-/-和Ctsk-cre分离的骨髓源性巨噬细胞(BMMs)的分化;与同窝对照小鼠相比,Trim21f/f小鼠在很大程度上受到损害。从机制上讲,YAP1/β-catenin信号被鉴定并证明是Trim21介导的BMSCs成骨分化所必需的。更重要的是,Trim21的缺失通过YAP1信号传导协调OBs和OC的偶联,阻止了卵巢切除术(OVX)和脂多糖(LPS)诱导的体内骨丢失。我们目前的研究表明,Trim21对调节OB介导的骨形成和OC介导的骨骼吸收至关重要,从而为探索Trim21作为治疗骨质疏松症和病理性骨丢失的新的双靶向方法提供了基础。
{"title":"Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling.","authors":"Ri-Xu Liu, Rong-He Gu, Zhi-Peng Li, Zhi-Quan Hao, Qin-Xiao Hu, Zhen-Yan Li, Xiao-Gang Wang, Wang Tang, Xiao-He Wang, Yu-Kai Zeng, Zhen-Wei Li, Qiu Dong, Xiao-Feng Zhu, Di Chen, Ke-Wei Zhao, Rong-Hua Zhang, Zhen-Gang Zha, Huan-Tian Zhang","doi":"10.1038/s41413-023-00296-3","DOIUrl":"10.1038/s41413-023-00296-3","url":null,"abstract":"<p><p>Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21<sup>-/-</sup>) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21<sup>-/-</sup> and Ctsk-cre; Trim21<sup>f/f</sup> mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10603047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54232458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
HuR-mediated nucleocytoplasmic translocation of HOTAIR relieves its inhibition of osteogenic differentiation and promotes bone formation. HuR介导的HOTAIR核质易位减轻了其对成骨分化的抑制并促进骨形成。
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-23 DOI: 10.1038/s41413-023-00289-2
Yuheng Li, Weijia Sun, Jianwei Li, Ruikai Du, Wenjuan Xing, Xinxin Yuan, Guohui Zhong, Dingsheng Zhao, Zizhong Liu, Xiaoyan Jin, Junjie Pan, Youyou Li, Qi Li, Guanghan Kan, Xuan Han, Shukuan Ling, Xiqing Sun, Yingxian Li

Bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation and osteoblast function play critical roles in bone formation, which is a highly regulated process. Long noncoding RNAs (lncRNAs) perform diverse functions in a variety of biological processes, including BMSC osteogenic differentiation. Although several studies have reported that HOX transcript antisense RNA (HOTAIR) is involved in BMSC osteogenic differentiation, its effect on bone formation in vivo remains unclear. Here, by constructing transgenic mice with BMSC (Prx1-HOTAIR)- and osteoblast (Bglap-HOTAIR)-specific overexpression of HOTAIR, we found that Prx1-HOTAIR and Bglap-HOTAIR transgenic mice show different bone phenotypes in vivo. Specifically, Prx1-HOTAIR mice showed delayed bone formation, while Bglap-HOTAIR mice showed increased bone formation. HOTAIR inhibits BMSC osteogenic differentiation but promotes osteoblast function in vitro. Furthermore, we identified that HOTAIR is mainly located in the nucleus of BMSCs and in the cytoplasm of osteoblasts. HOTAIR displays a nucleocytoplasmic translocation pattern during BMSC osteogenic differentiation. We first identified that the RNA-binding protein human antigen R (HuR) is responsible for HOTAIR nucleocytoplasmic translocation. HOTAIR is essential for osteoblast function, and cytoplasmic HOTAIR binds to miR-214 and acts as a ceRNA to increase Atf4 protein levels and osteoblast function. Bglap-HOTAIR mice, but not Prx1-HOTAIR mice, showed alleviation of bone loss induced by unloading. This study reveals the importance of temporal and spatial regulation of HOTAIR in BMSC osteogenic differentiation and bone formation, which provides new insights into precise regulation as a target for bone loss.

骨髓间充质干细胞(BMSC)的成骨分化和成骨细胞功能在骨形成中起着至关重要的作用,这是一个高度调控的过程。长链非编码RNA(lncRNA)在各种生物学过程中发挥着不同的功能,包括BMSC的成骨分化。尽管已有多项研究报道HOX转录物反义RNA(HOTAIR)参与BMSC的成骨分化,但其对体内骨形成的影响尚不清楚。在这里,通过构建具有BMSC(Prx1 HOTAIR)和成骨细胞(Bglap HOTIAR)特异性过表达HOTIAR的转基因小鼠,我们发现Prx1 HOTIAR和Bglap HOTAIR转基因小鼠在体内表现出不同的骨表型。具体而言,Prx1 HOTIAR小鼠表现出骨形成延迟,而Bglap HOTIAR鼠表现出骨生成增加。HOTAIR抑制BMSC成骨分化,但在体外促进成骨细胞功能。此外,我们发现HOTAIR主要位于BMSCs的细胞核和成骨细胞的细胞质中。HOTAIR在BMSC成骨分化过程中表现出核质易位模式。我们首先确定了人类抗原R(HuR)的RNA结合蛋白负责HOTAIR核质易位。HOTAIR对成骨细胞功能至关重要,细胞质HOTAIR与miR-214结合,并作为ceRNA增加Atf4蛋白水平和成骨细胞的功能。Bglap HOTAIR小鼠,而不是Prx1 HOTIAR小鼠,显示出减轻由卸载诱导的骨丢失。这项研究揭示了HOTAIR在BMSC成骨分化和骨形成中的时间和空间调控的重要性,为作为骨丢失靶点的精确调控提供了新的见解。
{"title":"HuR-mediated nucleocytoplasmic translocation of HOTAIR relieves its inhibition of osteogenic differentiation and promotes bone formation.","authors":"Yuheng Li, Weijia Sun, Jianwei Li, Ruikai Du, Wenjuan Xing, Xinxin Yuan, Guohui Zhong, Dingsheng Zhao, Zizhong Liu, Xiaoyan Jin, Junjie Pan, Youyou Li, Qi Li, Guanghan Kan, Xuan Han, Shukuan Ling, Xiqing Sun, Yingxian Li","doi":"10.1038/s41413-023-00289-2","DOIUrl":"10.1038/s41413-023-00289-2","url":null,"abstract":"<p><p>Bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation and osteoblast function play critical roles in bone formation, which is a highly regulated process. Long noncoding RNAs (lncRNAs) perform diverse functions in a variety of biological processes, including BMSC osteogenic differentiation. Although several studies have reported that HOX transcript antisense RNA (HOTAIR) is involved in BMSC osteogenic differentiation, its effect on bone formation in vivo remains unclear. Here, by constructing transgenic mice with BMSC (Prx1-HOTAIR)- and osteoblast (Bglap-HOTAIR)-specific overexpression of HOTAIR, we found that Prx1-HOTAIR and Bglap-HOTAIR transgenic mice show different bone phenotypes in vivo. Specifically, Prx1-HOTAIR mice showed delayed bone formation, while Bglap-HOTAIR mice showed increased bone formation. HOTAIR inhibits BMSC osteogenic differentiation but promotes osteoblast function in vitro. Furthermore, we identified that HOTAIR is mainly located in the nucleus of BMSCs and in the cytoplasm of osteoblasts. HOTAIR displays a nucleocytoplasmic translocation pattern during BMSC osteogenic differentiation. We first identified that the RNA-binding protein human antigen R (HuR) is responsible for HOTAIR nucleocytoplasmic translocation. HOTAIR is essential for osteoblast function, and cytoplasmic HOTAIR binds to miR-214 and acts as a ceRNA to increase Atf4 protein levels and osteoblast function. Bglap-HOTAIR mice, but not Prx1-HOTAIR mice, showed alleviation of bone loss induced by unloading. This study reveals the importance of temporal and spatial regulation of HOTAIR in BMSC osteogenic differentiation and bone formation, which provides new insights into precise regulation as a target for bone loss.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10593784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49688713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Prim-O-glucosylcimifugin ameliorates aging-impaired endogenous tendon regeneration by rejuvenating senescent tendon stem/progenitor cells. Prim-O-葡糖基cimifugin通过使衰老的肌腱干/祖细胞再生来改善衰老受损的内源性肌腱再生。
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-23 DOI: 10.1038/s41413-023-00288-3
Yu Wang, Shanshan Jin, Dan Luo, Danqing He, Min Yu, Lisha Zhu, Zixin Li, Liyuan Chen, Chengye Ding, Xiaolan Wu, Tianhao Wu, Weiran Huang, Xuelin Zhao, Meng Xu, Zhengwei Xie, Yan Liu

Adult tendon stem/progenitor cells (TSPCs) are essential for tendon maintenance, regeneration, and repair, yet they become susceptible to senescence with age, impairing the self-healing capacity of tendons. In this study, we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness. The top-ranked candidate, prim-O-glucosylcimifugin (POG), a saposhnikovia root extract, could ameliorate TPSC senescent phenotypes caused by long-term passage and natural aging in rats and humans, as well as restore the self-renewal and proliferative capacities and tenogenic potential of aged TSPCs. In vivo, the systematic administration of POG or the local delivery of POG nanoparticles functionally rescued endogenous tendon regeneration and repair in aged rats to levels similar to those of normal animals. Mechanistically, POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and decreasing mTOR signaling with the induction of autophagy. Thus, the strategy of pharmacological intervention with the deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons.

成年肌腱干/祖细胞(TSPC)对肌腱的维持、再生和修复至关重要,但随着年龄的增长,它们容易衰老,削弱肌腱的自我修复能力。在这项研究中,我们使用最近开发的基于深度学习的疗效预测系统,利用干性的转录特征,从天然产物中筛选潜在的干性促进和衰老抑制药物。排名第一的候选药物,原-O-葡糖基cimifugin(POG),一种saposhnikovia根提取物,可以改善由大鼠和人类的长期传代和自然衰老引起的TPSC衰老表型,并恢复衰老的TSPC的自我更新和增殖能力以及肌腱形成潜力。在体内,系统给予POG或局部递送POG纳米颗粒在功能上挽救了衰老大鼠的内源性肌腱再生和修复,使其达到与正常动物相似的水平。从机制上讲,POG通过同时抑制核因子-κB和降低mTOR信号传导和自噬诱导来保护TSPC在传代诱导和自然衰老过程中免受功能损伤。因此,用深度学习预测的化合物POG进行药物干预的策略可以使老年TSPC恢复活力,提高老年肌腱的再生能力。
{"title":"Prim-O-glucosylcimifugin ameliorates aging-impaired endogenous tendon regeneration by rejuvenating senescent tendon stem/progenitor cells.","authors":"Yu Wang, Shanshan Jin, Dan Luo, Danqing He, Min Yu, Lisha Zhu, Zixin Li, Liyuan Chen, Chengye Ding, Xiaolan Wu, Tianhao Wu, Weiran Huang, Xuelin Zhao, Meng Xu, Zhengwei Xie, Yan Liu","doi":"10.1038/s41413-023-00288-3","DOIUrl":"10.1038/s41413-023-00288-3","url":null,"abstract":"<p><p>Adult tendon stem/progenitor cells (TSPCs) are essential for tendon maintenance, regeneration, and repair, yet they become susceptible to senescence with age, impairing the self-healing capacity of tendons. In this study, we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness. The top-ranked candidate, prim-O-glucosylcimifugin (POG), a saposhnikovia root extract, could ameliorate TPSC senescent phenotypes caused by long-term passage and natural aging in rats and humans, as well as restore the self-renewal and proliferative capacities and tenogenic potential of aged TSPCs. In vivo, the systematic administration of POG or the local delivery of POG nanoparticles functionally rescued endogenous tendon regeneration and repair in aged rats to levels similar to those of normal animals. Mechanistically, POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and decreasing mTOR signaling with the induction of autophagy. Thus, the strategy of pharmacological intervention with the deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10593834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49688714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Association of mineral and bone biomarkers with adverse cardiovascular outcomes and mortality in the German Chronic Kidney Disease (GCKD) cohort. 德国慢性肾脏病(GCKD)队列中矿物质和骨骼生物标志物与不良心血管结局和死亡率的相关性。
1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-20 DOI: 10.1038/s41413-023-00291-8
Katharina Charlotte Reimer, Jennifer Nadal, Heike Meiselbach, Matthias Schmid, Ulla T Schultheiss, Fruzsina Kotsis, Helena Stockmann, Nele Friedrich, Matthias Nauck, Vera Krane, Kai-Uwe Eckardt, Markus P Schneider, Rafael Kramann, Jürgen Floege, Turgay Saritas

Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30-60 mL·min-1 per 1.73 m2 or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters (n = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35-2.30), CV death (HR 2.18, 95% CI: 1.50-3.16), MACE (HR 1.38, 95% CI: 1.12-1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56-2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality.

慢性肾脏疾病(CKD)中的矿物质和骨骼障碍(MBD)与心血管疾病(CVD)密切相关。在这项研究中,我们旨在比较九种MBD生物标志物的预后价值,以确定那些与不良心血管(CV)结果和死亡率最相关的生物标志物。在德国CKD(GCKD)研究的5217名参与者中,估计肾小球滤过率(eGFR)在30-60之间 每1.73m2或明显蛋白尿mL·min-1,基线时测量血清骨保护素(OPG)、C末端成纤维细胞生长因子-23(FGF23)、完整甲状旁腺激素(iPTH)、骨碱性磷酸酶(BAP)、1型胶原交联C末端肽(CTX1)、前胶原1完整N末端前肽(P1NP)、磷酸盐、钙和25-OH维生素D。这些参数中缺少值的参与者(n = 971名)被排除在外,总共留下4 246名参与者进行分析。在6.5年的中位随访中,观察到387例非心血管死亡、173例心血管死亡、645例非致命性主要心血管不良事件(MACE)和368例充血性心力衰竭(CHF)住院。OPG和FGF23与所有结果相关,其中OPG的风险比(HR)最高。在最终的Cox回归模型中,经心血管风险因素(包括肾功能和所有其他研究的生物标志物)调整后,OPG的每一个标准差增加都与非心血管死亡(HR 1.76,95%CI:13.5-2.30)、心血管死亡(HR2.18,95%CI:1.50-3.16)相关,MACE(HR 1.38,95%CI:1.12-1.71)和CHF住院(HR 2.05,95%CI:1.56-2.69。
{"title":"Association of mineral and bone biomarkers with adverse cardiovascular outcomes and mortality in the German Chronic Kidney Disease (GCKD) cohort.","authors":"Katharina Charlotte Reimer, Jennifer Nadal, Heike Meiselbach, Matthias Schmid, Ulla T Schultheiss, Fruzsina Kotsis, Helena Stockmann, Nele Friedrich, Matthias Nauck, Vera Krane, Kai-Uwe Eckardt, Markus P Schneider, Rafael Kramann, Jürgen Floege, Turgay Saritas","doi":"10.1038/s41413-023-00291-8","DOIUrl":"10.1038/s41413-023-00291-8","url":null,"abstract":"<p><p>Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30-60 mL·min<sup>-1</sup> per 1.73 m<sup>2</sup> or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters (n = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35-2.30), CV death (HR 2.18, 95% CI: 1.50-3.16), MACE (HR 1.38, 95% CI: 1.12-1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56-2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10587182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49685535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis. 双磷酸盐偶联西他沙星根除植入物相关骨髓炎小鼠模型中已建立的耐甲氧西林金黄色葡萄球菌感染和骨整合的证据。
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-18 DOI: 10.1038/s41413-023-00287-4
Youliang Ren, Jason Weeks, Thomas Xue, Joshua Rainbolt, Karen L de Mesy Bentley, Ye Shu, Yuting Liu, Elysia Masters, Philip Cherian, Charles E McKenna, Jeffrey Neighbors, Frank H Ebetino, Edward M Schwarz, Shuting Sun, Chao Xie

Eradication of MRSA osteomyelitis requires elimination of distinct biofilms. To overcome this, we developed bisphosphonate-conjugated sitafloxacin (BCS, BV600072) and hydroxybisphosphonate-conjugate sitafloxacin (HBCS, BV63072), which achieve "target-and-release" drug delivery proximal to the bone infection and have prophylactic efficacy against MRSA static biofilm in vitro and in vivo. Here we evaluated their therapeutic efficacy in a murine 1-stage exchange femoral plate model with bioluminescent MRSA (USA300LAC::lux). Osteomyelitis was confirmed by CFU on the explants and longitudinal bioluminescent imaging (BLI) after debridement and implant exchange surgery on day 7, and mice were randomized into seven groups: 1) Baseline (harvested at day 7, no treatment); 2) HPBP (bisphosphonate control for BCS) + vancomycin; 3) HPHBP (hydroxybisphosphonate control for HBCS) + vancomycin; 4) vancomycin; 5) sitafloxacin; 6) BCS + vancomycin; and 7) HBCS + vancomycin. BLI confirmed infection persisted in all groups except for mice treated with BCS or HBCS + vancomycin. Radiology revealed catastrophic femur fractures in all groups except mice treated with BCS or HBCS + vancomycin, which also displayed decreases in peri-implant bone loss, osteoclast numbers, and biofilm. To confirm this, we assessed the efficacy of vancomycin, sitafloxacin, and HBCS monotherapy in a transtibial implant model. The results showed complete lack of vancomycin efficacy while all mice treated with HBCS had evidence of infection control, and some had evidence of osseous integrated septic implants, suggestive of biofilm eradication. Taken together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate MRSA osteomyelitis.

根除MRSA骨髓炎需要清除不同的生物膜。为了克服这一点,我们开发了双磷酸盐偶联的西他沙星(BCS,BV600072)和羟基双磷酸盐偶联物西他氧氟沙星(HBCS,BV63072),它们实现了在骨感染近端的“靶向释放”药物递送,并在体外和体内对耐甲氧西林金黄色葡萄球菌静态生物膜具有预防作用。在这里,我们用生物发光MRSA(USA300LAC::lux)在小鼠1期交换股骨板模型中评估了它们的治疗效果。在第7天清创术和植入物交换手术后,通过外植体上的CFU和纵向生物发光成像(BLI)确认骨髓炎,并将小鼠随机分为七组:1)基线(第7天收获,无治疗);2) HPBP(BCS的双磷酸盐对照)+万古霉素;3) HPHBP(用于HBCS的羟基双磷酸盐对照)+万古霉素;4) 万古霉素;5) 西他沙星;6) BCS+万古霉素;和7)HBCS+万古霉素。除用BCS或HBCS+万古霉素治疗的小鼠外,BLI证实的感染在所有组中持续存在。放射学显示,除接受BCS或HBCS+万古霉素治疗的小鼠外,所有组均发生了灾难性股骨骨折,植入物周围的骨丢失、破骨细胞数量和生物膜也有所减少。为了证实这一点,我们评估了万古霉素、西他沙星和HBCS单药治疗在胫骨植入物模型中的疗效。结果显示,万古霉素完全没有疗效,而所有接受HBCS治疗的小鼠都有感染控制的证据,一些小鼠有骨整合脓毒症植入物的证据,这表明生物膜已经根除。总之,这些研究表明,HBCS辅助标准护理清创术和万古霉素治疗有可能根除MRSA骨髓炎。
{"title":"Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S. aureus infection with osseointegration in murine models of implant-associated osteomyelitis.","authors":"Youliang Ren, Jason Weeks, Thomas Xue, Joshua Rainbolt, Karen L de Mesy Bentley, Ye Shu, Yuting Liu, Elysia Masters, Philip Cherian, Charles E McKenna, Jeffrey Neighbors, Frank H Ebetino, Edward M Schwarz, Shuting Sun, Chao Xie","doi":"10.1038/s41413-023-00287-4","DOIUrl":"10.1038/s41413-023-00287-4","url":null,"abstract":"<p><p>Eradication of MRSA osteomyelitis requires elimination of distinct biofilms. To overcome this, we developed bisphosphonate-conjugated sitafloxacin (BCS, BV600072) and hydroxybisphosphonate-conjugate sitafloxacin (HBCS, BV63072), which achieve \"target-and-release\" drug delivery proximal to the bone infection and have prophylactic efficacy against MRSA static biofilm in vitro and in vivo. Here we evaluated their therapeutic efficacy in a murine 1-stage exchange femoral plate model with bioluminescent MRSA (USA300LAC::lux). Osteomyelitis was confirmed by CFU on the explants and longitudinal bioluminescent imaging (BLI) after debridement and implant exchange surgery on day 7, and mice were randomized into seven groups: 1) Baseline (harvested at day 7, no treatment); 2) HPBP (bisphosphonate control for BCS) + vancomycin; 3) HPHBP (hydroxybisphosphonate control for HBCS) + vancomycin; 4) vancomycin; 5) sitafloxacin; 6) BCS + vancomycin; and 7) HBCS + vancomycin. BLI confirmed infection persisted in all groups except for mice treated with BCS or HBCS + vancomycin. Radiology revealed catastrophic femur fractures in all groups except mice treated with BCS or HBCS + vancomycin, which also displayed decreases in peri-implant bone loss, osteoclast numbers, and biofilm. To confirm this, we assessed the efficacy of vancomycin, sitafloxacin, and HBCS monotherapy in a transtibial implant model. The results showed complete lack of vancomycin efficacy while all mice treated with HBCS had evidence of infection control, and some had evidence of osseous integrated septic implants, suggestive of biofilm eradication. Taken together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate MRSA osteomyelitis.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":12.7,"publicationDate":"2023-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10582111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41232267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Loss of Notch signaling in skeletal stem cells enhances bone formation with aging. 骨骼干细胞中Notch信号的缺失会随着衰老而增强骨形成。
1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-27 DOI: 10.1038/s41413-023-00283-8
Lindsey H Remark, Kevin Leclerc, Malissa Ramsukh, Ziyan Lin, Sooyeon Lee, Backialakshmi Dharmalingam, Lauren Gillinov, Vasudev V Nayak, Paulo El Parente, Margaux Sambon, Pablo J Atria, Mohamed A E Ali, Lukasz Witek, Alesha B Castillo, Christopher Y Park, Ralf H Adams, Aristotelis Tsirigos, Sophie M Morgani, Philipp Leucht

Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

骨骼干细胞和祖细胞(SSPCs)进行骨骼维护和修复。随着年龄的增长,它们产生的成骨细胞越来越少,脂肪细胞越来越多,导致骨骼完整性的丧失。这种有害转化的分子机制在很大程度上是未知的。单细胞RNA测序显示,在衰老过程中,SSPCs中的Notch信号传导升高。为了检测Notch活性增加的作用,我们在体内SSPCs中删除了Nicastrin,一种重要的Notch通路成分。中年条件敲除小鼠表现出SSPC骨谱系基因表达升高、骨小梁质量增加、骨髓肥胖减少和骨修复增强。因此,Notch调节SSPC细胞的命运决定,调节Notch信号可改善骨骼衰老表型,增加骨量,甚至超过年轻小鼠。最后,我们确定转录因子Ebf3是SSPCs中Notch信号传导的下游介体,它随着衰老而失调,强调它是一个很有前途的治疗靶点,可以使衰老的骨骼恢复活力。
{"title":"Loss of Notch signaling in skeletal stem cells enhances bone formation with aging.","authors":"Lindsey H Remark, Kevin Leclerc, Malissa Ramsukh, Ziyan Lin, Sooyeon Lee, Backialakshmi Dharmalingam, Lauren Gillinov, Vasudev V Nayak, Paulo El Parente, Margaux Sambon, Pablo J Atria, Mohamed A E Ali, Lukasz Witek, Alesha B Castillo, Christopher Y Park, Ralf H Adams, Aristotelis Tsirigos, Sophie M Morgani, Philipp Leucht","doi":"10.1038/s41413-023-00283-8","DOIUrl":"10.1038/s41413-023-00283-8","url":null,"abstract":"<p><p>Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10522593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41173100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Osteomodulin downregulation is associated with osteoarthritis development. 骨调节蛋白下调与骨关节炎的发展有关。
1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-20 DOI: 10.1038/s41413-023-00286-5
Jérémie Zappia, Qiao Tong, Renée Van der Cruyssen, Frederique M F Cornelis, Cécile Lambert, Tiago Pinto Coelho, Juliane Grisart, Erika Kague, Rik J Lories, Marc Muller, Dirk Elewaut, Chrissy L Hammond, Christelle Sanchez, Yves Henrotin

Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis (OA), and osteomodulin (OMD), a proteoglycan involved in extracellular matrix mineralization, is associated with the sclerotic phenotype. However, the functions of OMD remain poorly understood, specifically in vivo. We used Omd knockout and overexpressing male mice and mutant zebrafish to study its roles in bone and cartilage metabolism and in the development of OA. The expression of Omd is deeply correlated with bone and cartilage microarchitectures affecting the bone volume and the onset of subchondral bone sclerosis and spontaneous cartilage lesions. Mechanistically, OMD binds to RANKL and inhibits osteoclastogenesis, thus controlling the balance of bone remodeling. In conclusion, OMD is a key factor in subchondral bone sclerosis associated with OA. It participates in bone and cartilage homeostasis by acting on the regulation of osteoclastogenesis. Targeting OMD may be a promising new and personalized approach for OA.

导致硬化的软骨下骨重塑异常是骨关节炎(OA)的主要特征,骨调素(OMD)是一种参与细胞外基质矿化的蛋白聚糖,与硬化表型有关。然而,对OMD的功能仍知之甚少,尤其是在体内。我们使用Omd敲除和过表达雄性小鼠和突变斑马鱼来研究其在骨和软骨代谢以及OA发展中的作用。Omd的表达与影响骨体积、软骨下骨硬化和自发软骨损伤的骨和软骨微结构密切相关。从机制上讲,OMD与RANKL结合并抑制破骨细胞生成,从而控制骨重塑的平衡。总之,OMD是与OA相关的软骨下骨硬化的关键因素。它通过调节破骨细胞生成参与骨和软骨的稳态。针对OMD可能是一种很有前途的新的个性化OA方法。
{"title":"Osteomodulin downregulation is associated with osteoarthritis development.","authors":"Jérémie Zappia, Qiao Tong, Renée Van der Cruyssen, Frederique M F Cornelis, Cécile Lambert, Tiago Pinto Coelho, Juliane Grisart, Erika Kague, Rik J Lories, Marc Muller, Dirk Elewaut, Chrissy L Hammond, Christelle Sanchez, Yves Henrotin","doi":"10.1038/s41413-023-00286-5","DOIUrl":"10.1038/s41413-023-00286-5","url":null,"abstract":"<p><p>Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis (OA), and osteomodulin (OMD), a proteoglycan involved in extracellular matrix mineralization, is associated with the sclerotic phenotype. However, the functions of OMD remain poorly understood, specifically in vivo. We used Omd knockout and overexpressing male mice and mutant zebrafish to study its roles in bone and cartilage metabolism and in the development of OA. The expression of Omd is deeply correlated with bone and cartilage microarchitectures affecting the bone volume and the onset of subchondral bone sclerosis and spontaneous cartilage lesions. Mechanistically, OMD binds to RANKL and inhibits osteoclastogenesis, thus controlling the balance of bone remodeling. In conclusion, OMD is a key factor in subchondral bone sclerosis associated with OA. It participates in bone and cartilage homeostasis by acting on the regulation of osteoclastogenesis. Targeting OMD may be a promising new and personalized approach for OA.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10511717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41155982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
期刊
Bone Research
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1