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Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing. 在骨折愈合过程中,巨噬细胞与年龄相关的颗粒钙素分泌会诱导骨骼干细胞/祖细胞衰老。
IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-01-25 DOI: 10.1038/s41413-023-00309-1
Nan-Yu Zou, Ran Liu, Mei Huang, Yu-Rui Jiao, Jie Wei, Yangzi Jiang, Wen-Zhen He, Min Huang, Yi-Li Xu, Ling Liu, Yu-Chen Sun, Mi Yang, Qi Guo, Yan Huang, Tian Su, Ye Xiao, Wei-Shan Wang, Chao Zeng, Guang-Hua Lei, Xiang-Hang Luo, Chang-Jun Li

Skeletal stem/progenitor cell (SSPC) senescence is a major cause of decreased bone regenerative potential with aging, but the causes of SSPC senescence remain unclear. In this study, we revealed that macrophages in calluses secrete prosenescent factors, including grancalcin (GCA), during aging, which triggers SSPC senescence and impairs fracture healing. Local injection of human rGCA in young mice induced SSPC senescence and delayed fracture repair. Genetic deletion of Gca in monocytes/macrophages was sufficient to rejuvenate fracture repair in aged mice and alleviate SSPC senescence. Mechanistically, GCA binds to the plexin-B2 receptor and activates Arg2-mediated mitochondrial dysfunction, resulting in cellular senescence. Depletion of Plxnb2 in SSPCs impaired fracture healing. Administration of GCA-neutralizing antibody enhanced fracture healing in aged mice. Thus, our study revealed that senescent macrophages within calluses secrete GCA to trigger SSPC secondary senescence, and GCA neutralization represents a promising therapy for nonunion or delayed union in elderly individuals.

骨骼干/祖细胞(SSPC)衰老是随着年龄增长骨再生潜力下降的主要原因,但SSPC衰老的原因仍不清楚。在这项研究中,我们发现胼胝体中的巨噬细胞在衰老过程中会分泌包括粒钙蛋白(GCA)在内的前衰老因子,从而引发SSPC衰老并影响骨折愈合。向幼鼠局部注射人rGCA可诱导SSPC衰老并延迟骨折修复。遗传性删除单核细胞/巨噬细胞中的Gca足以使老龄小鼠的骨折修复恢复活力并缓解SSPC衰老。从机理上讲,GCA 与 plexin-B2 受体结合并激活 Arg2 介导的线粒体功能障碍,从而导致细胞衰老。SSPCs中Plxnb2的消耗会影响骨折愈合。给予 GCA 中和抗体可增强老年小鼠的骨折愈合。因此,我们的研究揭示了胼胝体中的衰老巨噬细胞会分泌 GCA 引发 SSPC 继发性衰老,而 GCA 中和是一种治疗老年人骨折不愈合或延迟愈合的有效方法。
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引用次数: 0
Transcriptional reprogramming during human osteoclast differentiation identifies regulators of osteoclast activity. 人类破骨细胞分化过程中的转录重编程确定了破骨细胞活性的调节因子。
IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-01-24 DOI: 10.1038/s41413-023-00312-6
Morten S Hansen, Kaja Madsen, Maria Price, Kent Søe, Yasunori Omata, Mario M Zaiss, Caroline M Gorvin, Morten Frost, Alexander Rauch

Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis, which is characterized by increased bone resorption and inadequate bone formation. As novel antiosteoporotic therapeutics are needed, understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets. This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation. Osteoclasts were differentiated from CD14+ monocytes from eight female donors. RNA sequencing during differentiation revealed 8 980 differentially expressed genes grouped into eight temporal patterns conserved across donors. These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs. Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks. The donor-specific expression patterns revealed genes at the monocyte stage, such as filamin B (FLNB) and oxidized low-density lipoprotein receptor 1 (OLR1, encoding LOX-1), that are predictive of the resorptive activity of mature osteoclasts. The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation, and these receptors are associated with bone mineral density SNPs, suggesting that they play a pivotal role in osteoclast differentiation and activity. The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1 (C5AR1), somatostatin receptor 2 (SSTR2), and free fatty acid receptor 4 (FFAR4/GPR120). Activating C5AR1 enhanced osteoclast formation, while activating SSTR2 decreased the resorptive activity of mature osteoclasts, and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts. In conclusion, we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity. These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets.

破骨细胞生成和破骨细胞活性的增强导致了骨质疏松症的发生,骨质疏松症的特点是骨吸收增加和骨形成不足。由于需要新型抗骨质疏松症疗法,了解人类破骨细胞生成的基因调控有助于确定潜在的治疗靶点。本研究旨在概述人类破骨细胞分化过程中的转录重编程。破骨细胞由来自八名女性供体的 CD14+ 单核细胞分化而来。分化过程中的 RNA 测序发现了 8 980 个差异表达基因,这些基因分为 8 个时间模式,在不同供体之间保持一致。这些模式揭示了与绝经后骨质疏松症易感基因相关的不同分子功能,这些易感基因基于髂嵴活检组织的 RNA 和骨矿物质密度 SNPs。网络分析揭示了时间表达模式之间的相互依赖关系,并提供了对亚型特异性转录网络的深入了解。供体特异性表达模式揭示了单核细胞阶段的基因,如丝胶素B(FLNB)和氧化低密度脂蛋白受体1(OLR1,编码LOX-1),这些基因可预测成熟破骨细胞的吸收活性。在破骨细胞分化过程中,差异表达的G蛋白偶联受体的表达很强,而且这些受体与骨矿物质密度SNPs相关,这表明它们在破骨细胞分化和活性中起着关键作用。体外药理学调节补体5A受体1(C5AR1)、体生长激素受体2(SSTR2)和游离脂肪酸受体4(FFAR4/GPR120),体现了三种不同表达的G蛋白偶联受体的调控作用。激活 C5AR1 会促进破骨细胞的形成,而激活 SSTR2 则会降低成熟破骨细胞的吸收活性,激活 FFAR4 则会降低成熟破骨细胞的数量和吸收活性。总之,我们报告了人类破骨细胞分化过程中转录重编程的发生,并确定 SSTR2 和 FFAR4 为抗吸收性 G 蛋白偶联受体,FLNB 和 LOX-1 为破骨细胞活性的潜在分子标记。这些数据有助于未来的研究确定破骨细胞分化和活性的分子调控因子,并为新的抗骨质疏松靶标奠定基础。
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引用次数: 0
The role and applications of extracellular vesicles in osteoporosis 细胞外囊泡在骨质疏松症中的作用和应用
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-01-23 DOI: 10.1038/s41413-023-00313-5
Fei Fang, Jie Yang, Jiahe Wang, Tiantian Li, Erxiang Wang, Demao Zhang, Xiaoheng Liu, Chenchen Zhou

Osteoporosis is a widely observed condition characterized by the systemic deterioration of bone mass and microarchitecture, which increases patient susceptibility to fragile fractures. The intricate mechanisms governing bone homeostasis are substantially impacted by extracellular vesicles (EVs), which play crucial roles in both pathological and physiological contexts. EVs derived from various sources exert distinct effects on osteoporosis. Specifically, EVs released by osteoblasts, endothelial cells, myocytes, and mesenchymal stem cells contribute to bone formation due to their unique cargo of proteins, miRNAs, and cytokines. Conversely, EVs secreted by osteoclasts and immune cells promote bone resorption and inhibit bone formation. Furthermore, the use of EVs as therapeutic modalities or biomaterials for diagnosing and managing osteoporosis is promising. Here, we review the current understanding of the impact of EVs on bone homeostasis, including the classification and biogenesis of EVs and the intricate regulatory mechanisms of EVs in osteoporosis. Furthermore, we present an overview of the latest research progress on diagnosing and treating osteoporosis by using EVs. Finally, we discuss the challenges and prospects of translational research on the use of EVs in osteoporosis.

骨质疏松症是一种被广泛观察到的疾病,其特点是骨量和微结构的系统性退化,这增加了患者对脆弱骨折的易感性。细胞外囊泡 (EVs) 对骨质平衡的复杂机制产生了重大影响,在病理和生理环境中都发挥着至关重要的作用。不同来源的细胞外囊泡对骨质疏松症有不同的影响。具体来说,成骨细胞、内皮细胞、肌细胞和间充质干细胞释放的EVs因其独特的蛋白质、miRNA和细胞因子载体而有助于骨形成。相反,破骨细胞和免疫细胞分泌的 EVs 会促进骨吸收,抑制骨形成。此外,将 EVs 用作诊断和管理骨质疏松症的治疗方法或生物材料也很有前景。在此,我们回顾了目前对 EVs 对骨稳态影响的理解,包括 EVs 的分类和生物生成以及 EVs 在骨质疏松症中错综复杂的调控机制。此外,我们还概述了利用 EVs 诊断和治疗骨质疏松症的最新研究进展。最后,我们讨论了利用 EVs 治疗骨质疏松症的转化研究面临的挑战和前景。
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引用次数: 0
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 CELL & TISSUE ENGINEERING 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 CELL & TISSUE ENGINEERING 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 CELL & TISSUE ENGINEERING 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 CELL & TISSUE ENGINEERING 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 CELL & TISSUE ENGINEERING 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 CELL & TISSUE ENGINEERING 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 CELL & TISSUE ENGINEERING 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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Bone Research
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