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Structure and function of the membrane microdomains in osteoclasts. 破骨细胞膜微结构域的结构与功能。
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2023-11-21 DOI: 10.1038/s41413-023-00294-5
Jialong Hou, Jian Liu, Zhixian Huang, Yining Wang, Hanbing Yao, Zhenxin Hu, Chengge Shi, Jiake Xu, Qingqing Wang

The cell membrane structure is closely related to the occurrence and progression of many metabolic bone diseases observed in the clinic and is an important target to the development of therapeutic strategies for these diseases. Strong experimental evidence supports the existence of membrane microdomains in osteoclasts (OCs). However, the potential membrane microdomains and the crucial mechanisms underlying their roles in OCs have not been fully characterized. Membrane microdomain components, such as scaffolding proteins and the actin cytoskeleton, as well as the roles of individual membrane proteins, need to be elucidated. In this review, we discuss the compositions and critical functions of membrane microdomains that determine the biological behavior of OCs through the three main stages of the OC life cycle.

细胞膜结构与临床观察到的许多代谢性骨病的发生和发展密切相关,是制定这些疾病治疗策略的重要靶点。强有力的实验证据支持破骨细胞(OCs)中膜微域的存在。然而,潜在的膜微结构域及其在OCs中作用的关键机制尚未完全表征。膜微结构域成分,如支架蛋白和肌动蛋白细胞骨架,以及单个膜蛋白的作用,需要阐明。在这篇综述中,我们讨论了膜微结构域的组成和关键功能,这些结构域决定了有机碳生命周期的三个主要阶段的生物行为。
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引用次数: 0
Annexin A5 derived from matrix vesicles protects against osteoporotic bone loss via mineralization. 来源于基质小泡的膜联蛋白A5通过矿化作用防止骨质疏松性骨丢失。
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2023-11-09 DOI: 10.1038/s41413-023-00290-9
Guanyue Su, Demao Zhang, Tiantian Li, Tong Pei, Jie Yang, Shasha Tu, Sijun Liu, Jie Ren, Yaojia Zhang, Mengmeng Duan, Xinrui Yang, Yang Shen, Chenchen Zhou, Jing Xie, Xiaoheng Liu

Matrix vesicles (MVs) have shown strong effects in diseases such as vascular ectopic calcification and pathological calcified osteoarthritis and in wound repair of the skeletal system due to their membranous vesicle characteristics and abundant calcium and phosphorus content. However, the role of MVs in the progression of osteoporosis is poorly understood. Here, we report that annexin A5, an important component of the matrix vesicle membrane, plays a vital role in bone matrix homeostasis in the deterioration of osteoporosis. We first identified annexin A5 from adherent MVs but not dissociative MVs of osteoblasts and found that it could be sharply decreased in the bone matrix during the occurrence of osteoporosis based on ovariectomized mice. We then confirmed its potential in mediating the mineralization of the precursor osteoblast lineage via its initial binding with collagen type I to achieve MV adhesion and the subsequent activation of cellular autophagy. Finally, we proved its protective role in resisting bone loss by applying it to osteoporotic mice. Taken together, these data revealed the importance of annexin A5, originating from adherent MVs of osteoblasts, in bone matrix remodeling of osteoporosis and provided a new strategy for the treatment and intervention of bone loss.

基质小泡(MV)由于其膜囊泡特性和丰富的钙磷含量,在血管异位钙化和病理性钙化性骨关节炎等疾病以及骨骼系统的伤口修复中显示出强大的作用。然而,MVs在骨质疏松症进展中的作用尚不清楚。在此,我们报道了膜联蛋白A5,基质囊泡膜的重要组成部分,在骨质疏松症恶化的骨基质稳态中发挥着至关重要的作用。我们首先从成骨细胞的粘附MV中鉴定了膜联蛋白A5,但没有从游离MV中鉴定,并发现在去卵巢小鼠的骨质疏松症发生过程中,它在骨基质中可能急剧减少。然后,我们证实了其通过与I型胶原的初始结合介导前体成骨细胞谱系矿化的潜力,以实现MV粘附和随后的细胞自噬激活。最后,我们通过将其应用于骨质疏松小鼠,证明了其在抵抗骨丢失方面的保护作用。总之,这些数据揭示了源自成骨细胞粘附MVs的膜联蛋白A5在骨质疏松症骨基质重塑中的重要性,并为骨丢失的治疗和干预提供了新的策略。
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引用次数: 0
Spatial transcriptomic interrogation of the murine bone marrow signaling landscape. 小鼠骨髓信号传导景观的空间转录组学研究。
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2023-11-06 DOI: 10.1038/s41413-023-00298-1
Xue Xiao, Conan Juan, Tingsheng Drennon, Cedric R Uytingco, Neda Vishlaghi, Dimitri Sokolowskei, Lin Xu, Benjamin Levi, Mimi C Sammarco, Robert J Tower

Self-renewal and differentiation of skeletal stem and progenitor cells (SSPCs) are tightly regulated processes, with SSPC dysregulation leading to progressive bone disease. While the application of single-cell RNA sequencing (scRNAseq) to the bone field has led to major advancements in our understanding of SSPC heterogeneity, stem cells are tightly regulated by their neighboring cells which comprise the bone marrow niche. However, unbiased interrogation of these cells at the transcriptional level within their native niche environment has been challenging. Here, we combined spatial transcriptomics and scRNAseq using a predictive modeling pipeline derived from multiple deconvolution packages in adult mouse femurs to provide an endogenous, in vivo context of SSPCs within the niche. This combined approach localized SSPC subtypes to specific regions of the bone and identified cellular components and signaling networks utilized within the niche. Furthermore, the use of spatial transcriptomics allowed us to identify spatially restricted activation of metabolic and major morphogenetic signaling gradients derived from the vasculature and bone surfaces that establish microdomains within the marrow cavity. Overall, we demonstrate, for the first time, the feasibility of applying spatial transcriptomics to fully mineralized tissue and present a combined spatial and single-cell transcriptomic approach to define the cellular components of the stem cell niche, identify cell‒cell communication, and ultimately gain a comprehensive understanding of local and global SSPC regulatory networks within calcified tissue.

骨骼干细胞和祖细胞(SSPCs)的自我更新和分化是一个受严格调控的过程,SSPCs失调会导致进行性骨病。虽然单细胞RNA测序(scRNAseq)在骨领域的应用使我们对SSPC异质性的理解取得了重大进展,但干细胞受到其邻近细胞的严格调控,这些细胞构成了骨髓小生境。然而,在这些细胞的天然生态位环境中,在转录水平上对其进行无偏见的询问一直是一项挑战。在这里,我们使用来自成年小鼠股骨中多个去卷积包的预测建模管道,将空间转录组学和scRNAseq相结合,以提供小众内SSPCs的内源性体内环境。这种联合方法将SSPC亚型定位到骨骼的特定区域,并确定了小众中使用的细胞成分和信号网络。此外,空间转录组学的使用使我们能够识别来源于血管系统和骨表面的代谢和主要形态发生信号梯度的空间限制性激活,这些信号梯度在骨髓腔内建立微结构域。总的来说,我们首次证明了将空间转录组学应用于完全矿化组织的可行性,并提出了一种空间和单细胞转录组学相结合的方法来定义干细胞生态位的细胞成分,识别细胞-细胞通讯,并最终全面了解钙化组织内的局部和全局SSPC调节网络。
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引用次数: 0
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。
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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 CELL & TISSUE ENGINEERING 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。
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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 CELL & TISSUE ENGINEERING 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。
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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 CELL & TISSUE ENGINEERING 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。
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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 CELL & TISSUE ENGINEERING 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。
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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 CELL & TISSUE ENGINEERING 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":"11 1","pages":"54"},"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 CELL & TISSUE ENGINEERING 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":"11 1","pages":"52"},"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}
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Bone Research
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