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A new perspective on intervertebral disc calcification—from bench to bedside 椎间盘钙化的新视角--从工作台到床边
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-22 DOI: 10.1038/s41413-023-00307-3
Emanuel J. Novais, Rajkishen Narayanan, Jose A. Canseco, Koen van de Wetering, Christopher K. Kepler, Alan S. Hilibrand, Alexander R. Vaccaro, Makarand V. Risbud

Disc degeneration primarily contributes to chronic low back and neck pain. Consequently, there is an urgent need to understand the spectrum of disc degeneration phenotypes such as fibrosis, ectopic calcification, herniation, or mixed phenotypes. Amongst these phenotypes, disc calcification is the least studied. Ectopic calcification, by definition, is the pathological mineralization of soft tissues, widely studied in the context of conditions that afflict vasculature, skin, and cartilage. Clinically, disc calcification is associated with poor surgical outcomes and back pain refractory to conservative treatment. It is frequently seen as a consequence of disc aging and progressive degeneration but exhibits unique molecular and morphological characteristics: hypertrophic chondrocyte-like cell differentiation; TNAP, ENPP1, and ANK upregulation; cell death; altered Pi and PPi homeostasis; and local inflammation. Recent studies in mouse models have provided a better understanding of the mechanisms underlying this phenotype. It is essential to recognize that the presentation and nature of mineralization differ between AF, NP, and EP compartments. Moreover, the combination of anatomic location, genetics, and environmental stressors, such as aging or trauma, govern the predisposition to calcification. Lastly, the systemic regulation of calcium and Pi metabolism is less important than the local activity of PPi modulated by the ANK-ENPP1 axis, along with disc cell death and differentiation status. While there is limited understanding of this phenotype, understanding the molecular pathways governing local intervertebral disc calcification may lead to developing disease-modifying drugs and better clinical management of degeneration-related pathologies.

椎间盘退变是导致慢性腰痛和颈痛的主要原因。因此,迫切需要了解椎间盘退变的各种表型,如纤维化、异位钙化、椎间盘突出或混合表型。在这些表型中,对椎间盘钙化的研究最少。异位钙化顾名思义是软组织的病理性矿化,在血管、皮肤和软骨的病变中被广泛研究。在临床上,椎间盘钙化与手术效果不佳和保守治疗无效的背痛有关。椎间盘钙化通常是椎间盘老化和进行性退变的结果,但具有独特的分子和形态学特征:肥大软骨细胞样细胞分化;TNAP、ENPP1 和 ANK 上调;细胞死亡;Pi 和 PPi 平衡改变;局部炎症。最近对小鼠模型的研究使人们对这种表型的机制有了更好的了解。必须认识到,AF、NP 和 EP 区间矿化的表现形式和性质各不相同。此外,解剖位置、遗传和环境压力因素(如衰老或创伤)共同作用,导致钙化倾向。最后,钙和π代谢的系统调控不如由ANK-ENPP1轴调控的PPi局部活性以及椎间盘细胞死亡和分化状态重要。虽然对这种表型的了解还很有限,但了解支配椎间盘局部钙化的分子途径可能有助于开发疾病调节药物和更好地临床治疗退变相关病症。
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引用次数: 0
MicroRNA-146a-loaded magnesium silicate nanospheres promote bone regeneration in an inflammatory microenvironment. 微RNA-146a负载硅酸镁纳米球促进炎症微环境中的骨再生
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-15 DOI: 10.1038/s41413-023-00299-0
Jiakang Yang, Jing Shuai, Lixuen Siow, Jingyi Lu, Miao Sun, Wenyue An, Mengfei Yu, Baixiang Wang, Qianming Chen

Reconstruction of irregular oral-maxillofacial bone defects with an inflammatory microenvironment remains a challenge, as chronic local inflammation can largely impair bone healing. Here, we used magnesium silicate nanospheres (MSNs) to load microRNA-146a-5p (miR-146a) to fabricate a nanobiomaterial, MSN+miR-146a, which showed synergistic promoting effects on the osteogenic differentiation of human dental pulp stem cells (hDPSCs). In addition, miR-146a exhibited an anti-inflammatory effect on mouse bone marrow-derived macrophages (BMMs) under lipopolysaccharide (LPS) stimulation by inhibiting the NF-κB pathway via targeting tumor necrosis factor receptor-associated factor 6 (TRAF6), and MSNs could simultaneously promote M2 polarization of BMMs. MiR-146a was also found to inhibit osteoclast formation. Finally, the dual osteogenic-promoting and immunoregulatory effects of MSN+miR-146a were further validated in a stimulated infected mouse mandibular bone defect model via delivery by a photocuring hydrogel. Collectively, the MSN+miR-146a complex revealed good potential in treating inflammatory irregular oral-maxillofacial bone defects.

在炎症微环境下重建不规则的口腔颌面骨缺损仍是一项挑战,因为慢性局部炎症会在很大程度上影响骨愈合。在这里,我们利用硅酸镁纳米球(MSNs)负载microRNA-146a-5p(miR-146a)来制造一种纳米生物材料MSN+miR-146a,它对人牙髓干细胞(hDPSCs)的成骨分化具有协同促进作用。此外,在脂多糖(LPS)刺激下,miR-146a通过靶向肿瘤坏死因子受体相关因子6(TRAF6)抑制NF-κB通路,对小鼠骨髓源性巨噬细胞(BMMs)具有抗炎作用,MSNs还能同时促进BMMs的M2极化。研究还发现 MiR-146a 可抑制破骨细胞的形成。最后,MSN+miR-146a的双重成骨促进和免疫调节作用在通过光固化水凝胶递送的受刺激感染小鼠下颌骨缺损模型中得到了进一步验证。总之,MSN+miR-146a 复合物在治疗炎症性不规则口腔颌面骨缺损方面具有良好的潜力。
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引用次数: 0
Estradiol increases cortical and trabecular bone accrual and bone strength in an adolescent male-to-female mouse model of gender-affirming hormone therapy 雌二醇可增加青少年雄性变雌性小鼠性别确认激素疗法模型的皮质骨和骨小梁增生以及骨强度
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-01-11 DOI: 10.1038/s41413-023-00308-2
Tian Nie, Varun S. Venkatesh, Suzanne Golub, Kathryn S. Stok, Haniyeh Hemmatian, Reena Desai, David J. Handelsman, Jeffrey D. Zajac, Mathis Grossmann, Rachel A. Davey

The effects of gender-affirming hormone therapy on the skeletal integrity and fracture risk in transitioning adolescent trans girls are unknown. To address this knowledge gap, we developed a mouse model to simulate male-to-female transition in human adolescents in whom puberty is first arrested by using gonadotrophin-releasing hormone analogs with subsequent estradiol treatment. Puberty was suppressed by orchidectomy in male mice at 5 weeks of age. At 3 weeks post-surgery, male-to-female mice were treated with a high dose of estradiol (~0.85 mg) by intraperitoneal silastic implantation for 12 weeks. Controls included intact and orchidectomized males at 3 weeks post-surgery, vehicle-treated intact males, intact females and orchidectomized males at 12 weeks post-treatment. Compared to male controls, orchidectomized males exhibited decreased peak bone mass accrual and a decreased maximal force the bone could withstand prior to fracture. Estradiol treatment in orchidectomized male-to-female mice compared to mice in all control groups was associated with an increased cortical thickness in the mid-diaphysis, while the periosteal circumference increased to a level that was intermediate between intact male and female controls, resulting in increased maximal force and stiffness. In trabecular bone, estradiol treatment increased newly formed trabeculae arising from the growth plate as well as mineralizing surface/bone surface and bone formation rate, consistent with the anabolic action of estradiol on osteoblast proliferation. These data support the concept that skeletal integrity can be preserved and that long-term fractures may be prevented in trans girls treated with GnRHa and a sufficiently high dose of GAHT. Further study is needed to identify an optimal dose of estradiol that protects the bone without adverse side effects.

性别确认激素疗法对变性少女骨骼完整性和骨折风险的影响尚不清楚。为了填补这一知识空白,我们开发了一种小鼠模型,通过使用促性腺激素释放激素类似物和随后的雌二醇治疗来模拟人类青少年的男变女过程。对 5 周大的雄性小鼠进行睾丸切除术,抑制其青春期。手术后 3 周,雄性变雌性小鼠腹腔植入高剂量雌二醇(约 0.85 毫克),持续 12 周。对照组包括手术后 3 周的完整雄性小鼠和睾丸切除雄性小鼠、接受药物治疗的完整雄性小鼠、治疗后 12 周的完整雌性小鼠和睾丸切除雄性小鼠。与雄性对照组相比,睾丸切除的雄性动物表现出峰值骨量减少,骨折前骨骼可承受的最大力也减少。与所有对照组的小鼠相比,睾丸切除的雄性变雌性小鼠接受雌二醇治疗后,干骺端中部的皮质厚度增加,而骨膜周长增加到介于完整雄性对照组和雌性对照组之间的水平,从而增加了最大力和硬度。在骨小梁中,雌二醇治疗增加了生长板上新形成的骨小梁以及矿化面/骨面和骨形成率,这与雌二醇对成骨细胞增殖的同化作用是一致的。这些数据支持了这样一个概念,即用 GnRHa 和足够高剂量的 GAHT 治疗反式女孩,可以保持骨骼的完整性,并可预防长期骨折。还需要进一步研究,以确定既能保护骨骼又无不良副作用的最佳雌二醇剂量。
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引用次数: 0
Neuro–bone tissue engineering: emerging mechanisms, potential strategies, and current challenges 神经骨组织工程:新兴机制、潜在战略和当前挑战
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-12-20 DOI: 10.1038/s41413-023-00302-8
Wenzhe Sun, Bing Ye, Siyue Chen, Lian Zeng, Hongwei Lu, Yizhou Wan, Qing Gao, Kaifang Chen, Yanzhen Qu, Bin Wu, Xiao Lv, Xiaodong Guo

The skeleton is a highly innervated organ in which nerve fibers interact with various skeletal cells. Peripheral nerve endings release neurogenic factors and sense skeletal signals, which mediate bone metabolism and skeletal pain. In recent years, bone tissue engineering has increasingly focused on the effects of the nervous system on bone regeneration. Simultaneous regeneration of bone and nerves through the use of materials or by the enhancement of endogenous neurogenic repair signals has been proven to promote functional bone regeneration. Additionally, emerging information on the mechanisms of skeletal interoception and the central nervous system regulation of bone homeostasis provide an opportunity for advancing biomaterials. However, comprehensive reviews of this topic are lacking. Therefore, this review provides an overview of the relationship between nerves and bone regeneration, focusing on tissue engineering applications. We discuss novel regulatory mechanisms and explore innovative approaches based on nerve–bone interactions for bone regeneration. Finally, the challenges and future prospects of this field are briefly discussed.

骨骼是一个高度神经支配的器官,其中的神经纤维与各种骨骼细胞相互作用。外周神经末梢释放神经原因子,感知骨骼信号,从而介导骨代谢和骨骼疼痛。近年来,骨组织工程学越来越关注神经系统对骨再生的影响。事实证明,通过使用材料或增强内源性神经修复信号来实现骨与神经的同时再生,可促进功能性骨再生。此外,有关骨骼互感机制和中枢神经系统对骨平衡调节的新信息也为生物材料的发展提供了机遇。然而,目前还缺乏对这一主题的全面综述。因此,本综述概述了神经与骨再生之间的关系,重点关注组织工程应用。我们讨论了新的调控机制,并探讨了基于神经与骨相互作用的骨再生创新方法。最后,简要讨论了这一领域的挑战和未来前景。
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引用次数: 0
Sensory nerves directly promote osteoclastogenesis by secreting peptidyl-prolyl cis-trans isomerase D (Cyp40) 感觉神经通过分泌肽基脯氨酰顺反异构酶 D(Cyp40)直接促进破骨细胞生成
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-12-14 DOI: 10.1038/s41413-023-00300-w
Junqin Li, Bin Liu, Hao Wu, Shuaishuai Zhang, Zhuowen Liang, Shuo Guo, Huijie Jiang, Yue Song, Xing Lei, Yi Gao, Pengzhen Cheng, Donglin Li, Jimeng Wang, Yang Liu, Di Wang, Nazhi Zhan, Jing Xu, Lin Wang, Guozhi Xiao, Liu Yang, GuoXian Pei

Given afferent functions, sensory nerves have recently been found to exert efferent effects and directly alter organ physiology. Additionally, several studies have highlighted the indirect but crucial role of sensory nerves in the regulation of the physiological function of osteoclasts. Nonetheless, evidence regarding the direct sensory nerve efferent influence on osteoclasts is lacking. In the current study, we found that high levels of efferent signals were transported directly from the sensory nerves into osteoclasts. Furthermore, sensory hypersensitivity significantly increased osteoclastic bone resorption, and sensory neurons (SNs) directly promoted osteoclastogenesis in an in vitro coculture system. Moreover, we screened a novel neuropeptide, Cyp40, using an isobaric tag for relative and absolute quantitation (iTRAQ). We observed that Cyp40 is the efferent signal from sensory nerves, and it plays a critical role in osteoclastogenesis via the aryl hydrocarbon receptor (AhR)-Ras/Raf-p-Erk-NFATc1 pathway. These findings revealed a novel mechanism regarding the influence of sensory nerves on bone regulation, i.e., a direct promoting effect on osteoclastogenesis by the secretion of Cyp40. Therefore, inhibiting Cyp40 could serve as a strategy to improve bone quality in osteoporosis and promote bone repair after bone injury.

由于感觉神经具有传入功能,最近发现它还能产生传出效应,直接改变器官的生理机能。此外,一些研究强调了感觉神经在调节破骨细胞生理功能中间接但关键的作用。然而,关于感觉神经传出对破骨细胞的直接影响还缺乏证据。在本研究中,我们发现高水平的传出信号直接从感觉神经传入破骨细胞。此外,感觉过敏会明显增加破骨细胞的骨吸收,感觉神经元(SNs)会在体外共培养系统中直接促进破骨细胞的生成。此外,我们还利用相对和绝对定量异位标签(iTRAQ)筛选了一种新型神经肽--Cyp40。我们观察到,Cyp40是来自感觉神经的传出信号,它通过芳基烃受体(AhR)-Ras/Raf-p-Erk-NFATc1途径在破骨细胞生成过程中发挥关键作用。这些发现揭示了感觉神经影响骨调节的新机制,即通过分泌Cyp40直接促进破骨细胞生成。因此,抑制Cyp40可作为改善骨质疏松症患者骨质量和促进骨损伤后骨修复的一种策略。
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引用次数: 0
Risk of metabolic abnormalities in osteoarthritis: a new perspective to understand its pathological mechanisms. 骨关节炎代谢异常的风险:了解其病理机制的新视角。
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-12-06 DOI: 10.1038/s41413-023-00301-9
Guizheng Wei, Ke Lu, Muhammad Umar, Zhenglin Zhu, William W Lu, John R Speakman, Yan Chen, Liping Tong, Di Chen

Although aging has traditionally been viewed as the most important risk factor for osteoarthritis (OA), an increasing amount of epidemiological evidence has highlighted the association between metabolic abnormalities and OA, particularly in younger individuals. Metabolic abnormalities, such as obesity and type II diabetes, are strongly linked to OA, and they affect both weight-bearing and non-weight-bearing joints, thus suggesting that the pathogenesis of OA is more complicated than the mechanical stress induced by overweight. This review aims to explore the recent advances in research on the relationship between metabolic abnormalities and OA risk, including the impact of abnormal glucose and lipid metabolism, the potential pathogenesis and targeted therapeutic strategies.

尽管衰老历来被视为骨关节炎(OA)最重要的风险因素,但越来越多的流行病学证据强调了代谢异常与 OA 之间的关联,尤其是在年轻人中。代谢异常(如肥胖和 II 型糖尿病)与 OA 关系密切,它们既影响负重关节,也影响非负重关节,因此表明 OA 的发病机制比超重引起的机械压力更为复杂。本综述旨在探讨代谢异常与 OA 风险之间关系的最新研究进展,包括糖脂代谢异常的影响、潜在发病机制和靶向治疗策略。
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引用次数: 0
Lipolysis supports bone formation by providing osteoblasts with endogenous fatty acid substrates to maintain bioenergetic status. 脂肪分解通过为成骨细胞提供内源性脂肪酸底物来维持生物能量状态,从而支持骨形成。
IF 12.7 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-11-24 DOI: 10.1038/s41413-023-00297-2
Ananya Nandy, Ron C M Helderman, Santosh Thapa, Shobana Jayapalan, Alison Richards, Nikita Narayani, Michael P Czech, Clifford J Rosen, Elizabeth Rendina-Ruedy

Bone formation is a highly energy-demanding process that can be impacted by metabolic disorders. Glucose has been considered the principal substrate for osteoblasts, although fatty acids are also important for osteoblast function. Here, we report that osteoblasts can derive energy from endogenous fatty acids stored in lipid droplets via lipolysis and that this process is critical for bone formation. As such, we demonstrate that osteoblasts accumulate lipid droplets that are highly dynamic and provide the molecular mechanism by which they serve as a fuel source for energy generation during osteoblast maturation. Inhibiting cytoplasmic lipolysis leads to both an increase in lipid droplet size in osteoblasts and an impairment in osteoblast function. The fatty acids released by lipolysis from these lipid droplets become critical for cellular energy production as cellular energetics shifts towards oxidative phosphorylation during nutrient-depleted conditions. In vivo, conditional deletion of the ATGL-encoding gene Pnpla2 in osteoblast progenitor cells reduces cortical and trabecular bone parameters and alters skeletal lipid metabolism. Collectively, our data demonstrate that osteoblasts store fatty acids in the form of lipid droplets, which are released via lipolysis to support cellular bioenergetic status when nutrients are limited. Perturbations in this process result in impairment of bone formation, specifically reducing ATP production and overall osteoblast function.

骨形成是一个高能量需求的过程,可能受到代谢紊乱的影响。葡萄糖被认为是成骨细胞的主要底物,尽管脂肪酸对成骨细胞的功能也很重要。在这里,我们报道成骨细胞可以通过脂肪分解从储存在脂滴中的内源性脂肪酸中获得能量,这一过程对骨形成至关重要。因此,我们证明了成骨细胞积累的脂滴是高度动态的,并提供了分子机制,通过这种机制,它们在成骨细胞成熟过程中作为能量产生的燃料来源。抑制细胞质脂解导致成骨细胞脂滴大小的增加和成骨细胞功能的损害。在营养匮乏的条件下,当细胞能量转换为氧化磷酸化时,脂滴分解释放的脂肪酸对细胞能量产生至关重要。在体内,成骨细胞祖细胞中atgl编码基因Pnpla2的条件缺失会降低骨皮质和骨小梁参数,并改变骨骼脂质代谢。总的来说,我们的数据表明,成骨细胞以脂滴的形式储存脂肪酸,当营养物质有限时,脂滴通过脂肪分解释放,以支持细胞的生物能量状态。这一过程中的扰动导致骨形成受损,特别是减少ATP的产生和整体成骨细胞的功能。
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引用次数: 0
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 Biochemistry, Genetics and Molecular Biology 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 Biochemistry, Genetics and Molecular Biology 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 Biochemistry, Genetics and Molecular Biology 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
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Bone Research
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