Journal of Orthopaedic Translation最新文献

Failure analysis and design improvement of retrieved plates from revision surgery 翻修手术中取出的钢板的故障分析和设计改进

IF 5.9 1区医学 Q1 ORTHOPEDICS

Journal of Orthopaedic Translation

Pub Date : 2024-09-27 DOI: 10.1016/j.jot.2024.08.011

Background

The fracture of bone plate can cause considerable pain for the patient and increase the burden on the public finances. This study aims to explore the failure mechanism of 49 plates retrieved from revision surgery and introduce pure magnesium (Mg) block to improve the biomechanical performance of the plate via decreasing the stiffness and to stimulate the biological response of the plate potentially by the degradation of Mg block.

Methods

The morphological analysis and component analysis of the plates were conducted to determine the fracture reason of the plates combining the clinical data. According to the structural feature, the 49 retrieved plates were divided into: traditional plate (TP), asymmetrical plate (AP), reconstructive plate (RP) and central enhancement plate (CEP), and their structure features are normalized in a commercial plate, respectively. The biomechanical performance of the plates was evaluated using a validated femoral finite element model. A block of pure Mg with a thickness of 1 mm, 1.5 mm and 2 mm was also incorporated into the CEP to be assessed.

Results

The results indicated that the retrieved plates mainly failed due to fatigue fracture induced by delayed union or nonunion (44/49), and using pure titanium plates in weight-bearing areas increased the risk of fracture compared with Ti alloy plates when the delayed union or nonunion occurred. The TP demonstrated the highest compression resistance and bending resistance, while CEP had the highest rotational resistance. As the thickness of the Mg block was increased, the stress on the plate in compression decreased, but the stress in rotation increased. The plate with a 1.5 mm Mg block demonstrated excellent compression resistance, bending resistance and rotational resistance.

Conclusion

Fatigue fracture resulting from the delayed union or nonunion is the primary failure reason of plates in clinic. The incorporation of Mg block into plate improves the biomechanical performance and has the potential to promote bone healing. The plate with a 1.5 mm Mg block may be suitable for use in orthopaedics.

The translational potential of this article

This study assessed the failure mechanism of retrieved bone plates and used this data to develop a novel plate incorporating a 1.5 mm block of pure Mg block at the position corresponding to the fracture line. The novel plate exhibited excellent compression resistance, bending resistance and rotational resistance due to the alleviation of stress concentrations. The Mg block has the potential to degrade over time to promote fracture healing and prevents fatigue fracture of plates.

背景骨板骨折会给患者带来巨大痛苦，并增加公共财政负担。本研究旨在探讨翻修手术中取出的 49 块骨板的断裂机制，并引入纯镁块，通过降低刚度改善骨板的生物力学性能，并通过镁块的降解潜在地刺激骨板的生物反应。方法对骨板进行形态分析和成分分析，结合临床数据确定骨板的断裂原因。根据结构特征，将检索到的 49 块钢板分为：传统钢板（TP）、非对称钢板（AP）、重建钢板（RP）和中央增强钢板（CEP），并分别将其结构特征归一化为商用钢板。使用经过验证的股骨有限元模型对这些钢板的生物力学性能进行了评估。结果表明，回收的钢板主要因延迟结合或不结合引起的疲劳断裂而失效（44/49），与钛合金钢板相比，在发生延迟结合或不结合时，在负重区使用纯钛钢板会增加骨折风险。TP 具有最高的抗压性和抗弯性，而 CEP 具有最高的抗旋转性。随着镁块厚度的增加，钢板的压缩应力降低，但旋转应力增加。带有 1.5 毫米镁块的钢板具有出色的抗压、抗弯和抗旋转性能。在钢板中加入镁块可改善生物力学性能，并具有促进骨愈合的潜力。这项研究评估了取骨钢板的失效机制，并利用这些数据开发了一种新型钢板，在骨折线相应位置加入了1.5毫米的纯镁块。由于减轻了应力集中，新型骨板表现出优异的抗压、抗弯和抗旋转性能。镁块具有随时间降解的潜力，可促进断裂愈合，防止钢板疲劳断裂。

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引用次数: 0

Emerging role of liver-bone axis in osteoporosis 肝-骨轴在骨质疏松症中的新作用

IF 5.9 1区医学 Q1 ORTHOPEDICS

Journal of Orthopaedic Translation

Pub Date : 2024-09-01 DOI: 10.1016/j.jot.2024.07.008

Background

Increasing attention to liver-bone crosstalk has spurred interest in targeted interventions for various forms of osteoporosis. Liver injury induced by different liver diseases can cause an imbalance in bone metabolism, indicating a novel regulatory paradigm between the liver and bone. However, the role of the liver-bone axis in both primary and secondary osteoporosis remains inadequately elucidated. Therefore, exploring the exact regulatory mechanisms of the liver-bone axis may offer innovative clinical approaches for treating diseases associated with the liver and bone.

Methods

Here, we summarize the latest research on the liver-bone axis by searching the PubMed and Web of Science databases and discuss the possible mechanism of the liver-bone axis in different types of osteoporosis. The literature directly reporting the regulatory role of the liver-bone axis in different types of osteoporosis from the PubMed and Web of Science databases has been included in the discussion of this review (including but not limited to the definition of the liver-bone axis, clinical studies, and basic research). In addition, articles discussing changes in bone metabolism caused by different etiologies of liver injury have also been included in the discussion of this review (including but not limited to clinical studies and basic research).

Results

Several endocrine factors (IGF-1, FGF21, hepcidin, vitamin D, osteocalcin, OPN, LCAT, Fetuin-A, PGs, BMP2/9, IL-1/6/17, and TNF-α) and key genes (SIRT2, ABCB4, ALDH2, TFR2, SPTBN1, ZNF687 and SREBP2) might be involved in the regulation of the liver-bone axis. In addition to the classic metabolic pathways involved in inflammation and oxidative stress, iron metabolism, cholesterol metabolism, lipid metabolism and immunometabolism mediated by the liver-bone axis require more research to elucidate the regulatory mechanisms involved in osteoporosis.

Conclusion

During primary and secondary osteoporosis, the liver-bone axis is responsible for liver and bone homeostasis via several hepatokines and osteokines as well as biochemical signaling. Combining multiomics technology and data mining technology could further advance our understanding of the liver-bone axis, providing new clinical strategies for managing liver and bone-related diseases.

The translational potential of this article is as follows: Abnormal metabolism in the liver could seriously affect the metabolic imbalance of bone. This review summarizes the indispensable role of several endocrine factors and biochemical signaling pathways involved in the liver-bone axis and emphasizes the important role of liver metabolic homeostasis in the pathogenesis of osteoporosis, which provides novel potential directions for the prevention, diagnosis, and treatment of liver and bone-related diseases.

背景肝与骨之间的相互影响日益受到关注，这激发了人们对各种形式骨质疏松症进行有针对性干预的兴趣。不同肝病引起的肝损伤可导致骨代谢失衡，这表明肝与骨之间存在一种新的调节模式。然而，肝-骨轴在原发性和继发性骨质疏松症中的作用仍未得到充分阐明。因此，探索肝骨轴的确切调控机制可能为治疗肝脏和骨骼相关疾病提供创新的临床方法。方法在此，我们通过检索PubMed和Web of Science数据库，总结了有关肝骨轴的最新研究，并讨论了肝骨轴在不同类型骨质疏松症中的可能机制。PubMed和Web of Science数据库中直接报道肝骨轴在不同类型骨质疏松症中调控作用的文献已纳入本综述的讨论范围（包括但不限于肝骨轴的定义、临床研究和基础研究）。此外，本综述还收录了讨论不同肝损伤病因引起的骨代谢变化的文章（包括但不限于临床研究和基础研究）。结果一些内分泌因子（IGF-1、FGF21、肝素、维生素 D、骨钙素、OPN、LCAT、Fetuin-A、PGs、BMP2/9、IL-1/6/17 和 TNF-α）和关键基因（SIRT2、ABCB4、ALDH2、TFR2、SPTBN1、ZNF687 和 SREBP2）可能参与了肝-骨轴的调控。除了涉及炎症和氧化应激的经典代谢途径外，肝骨轴介导的铁代谢、胆固醇代谢、脂质代谢和免疫代谢也需要更多的研究，以阐明骨质疏松症的调控机制。结合多组学技术和数据挖掘技术，可以进一步推动我们对肝骨轴的理解，为治疗肝脏和骨骼相关疾病提供新的临床策略：肝脏代谢异常会严重影响骨骼的代谢失衡。这篇综述总结了肝-骨轴中涉及的几种内分泌因子和生化信号通路的不可或缺的作用，强调了肝脏代谢平衡在骨质疏松症发病机制中的重要作用，为肝脏和骨骼相关疾病的预防、诊断和治疗提供了新的潜在方向。

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引用次数: 0

Biomarkers for hypertrophic chondrocyte differentiation are associated with spatial cellular organisation and suggest endochondral ossification-like processes in osteoarthritic cartilage: An exploratory study 肥大软骨细胞分化的生物标志物与空间细胞组织有关，表明骨关节炎软骨中存在类似软骨内骨化的过程：一项探索性研究

IF 5.9 1区医学 Q1 ORTHOPEDICS

Journal of Orthopaedic Translation

Pub Date : 2024-09-01 DOI: 10.1016/j.jot.2024.08.006

Background

In healthy articular cartilage, chondrocytes are found along arcades of collagen fibers as Single Strings. With onset of cartilage degeneration this pattern changes to Double Strings. In the course of osteoarthritis Small Clusters, and finally Big Clusters form. In highly degenerated articular cartilage, another poorly understood pattern is found where chondrocyte morphology differs considerably, and the distribution of cells is diffuse. Progression of osteoarthritis is accompanied by key processes such as chondrocyte proliferation, apoptosis, hypertrophic differentiation, inflammation, and angiogenesis. The aim of this exploratory study was to identify biomarkers for these processes in the context of spatial cellular organizational changes in articular cartilage.

Methods

Cartilage explants (n = 166 patients) were sorted according to their predominant cellular pattern. Quantitative or semi-quantitative analysis of 39 biomarkers were performed by multiplex assay (31) or ELISA (8), and qualitative analysis on 12 immunohistochemical markers.

Results

Hypertrophic differentiation (e.g. type-X collagen, osteopontin, osteocalcin and interleukin-6) and angiogenesis were associated with changes in chondrocyte organisation. First changes take place already at the transition from Single Strings to Double Strings. Drastic changes in the appearance of numerous biomarkers are found at the transition from Big Clusters to Diffuse.

Conclusion

Key processes in osteoarthritis and their biomarkers seem to depend on the spatial distribution of chondrocytes in articular cartilage. Abrupt changes in biomarker occurrence were observed between Big Clusters and Diffuse insinuating that the Diffuse pattern is composed of a different cell population or at least a different form of chondrocyte morphology.

The Translational Potential of this Article

In situ identification of the different spatial chondrocyte patterns by fluorescence microscopy has already been established in the recent past. Analysing human in-situ cartilage explants rather than isolated OA chondrocytes closes the gap between in vitro and in vivo studies and as such, stretches a big step towards translation of the observed findings. The direct association between tissue biomarker profile and cellular arrangements representing different states of OA sheds new light on the molecular and cellular physiopathology, especially in the context of larger processes such as angiogenesis, cellular proliferation, differentiation, and apoptosis. This also opens an interesting perspective for future investigation of such biomarkers and processes in clinical studies.

背景在健康的关节软骨中，软骨细胞沿着胶原纤维弧线分布，呈单串状。随着软骨变性的发生，这种模式变为双串。在骨关节炎的过程中，会形成小簇，最后形成大簇。在高度退化的关节软骨中，发现了另一种鲜为人知的模式，即软骨细胞形态差异很大，细胞分布呈弥散状。骨关节炎的进展伴随着软骨细胞增殖、凋亡、肥大分化、炎症和血管生成等关键过程。这项探索性研究的目的是在关节软骨空间细胞组织变化的背景下确定这些过程的生物标志物。结果肥大分化（如 X 型胶原、骨生成素、骨钙素和白细胞介素-6）和血管生成与软骨细胞组织的变化有关。最初的变化发生在从单股到双股的过渡阶段。结论骨关节炎的关键过程及其生物标志物似乎取决于软骨细胞在关节软骨中的空间分布。通过荧光显微镜对不同空间软骨细胞形态的原位识别在最近已经得到证实。对人体原位软骨外植体而非分离的OA软骨细胞进行分析，缩小了体外研究与体内研究之间的差距，因此在转化观察结果方面迈出了一大步。组织生物标志物特征与代表 OA 不同状态的细胞排列之间的直接联系，为分子和细胞生理病理学，尤其是血管生成、细胞增殖、分化和凋亡等更大的过程提供了新的视角。这也为今后在临床研究中对此类生物标志物和过程进行调查开辟了一个有趣的视角。

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引用次数: 0

Corrigendum to ‘JD-312 – A novel small molecule that facilitates cartilage repair and alleviates osteoarthritis progression’[Journal of Orthopaedic Translation 44 (2024) 60–71] JD-312--一种促进软骨修复并缓解骨关节炎进展的新型小分子"[《骨科转化杂志》44 (2024) 60-71] 更正

IF 5.9 1区医学 Q1 ORTHOPEDICS

Journal of Orthopaedic Translation

Pub Date : 2024-09-01 DOI: 10.1016/j.jot.2024.08.017

引用次数: 0

Corrigendum to “Sirt1 protects against intervertebral disc degeneration induced by 1,25-Dihydroxyvitamin D insufficiency in mice by inhibiting the NF-κB inflammatory pathway”[Journal of Orthopaedic Translation 40 (2023) 13–26] Sirt1通过抑制NF-κB炎症通路保护小鼠免受1,25-二羟基维生素D不足诱发的椎间盘退变》[《骨科转化杂志》40 (2023) 13-26] 更正

IF 5.9 1区医学 Q1 ORTHOPEDICS

Journal of Orthopaedic Translation

Pub Date : 2024-09-01 DOI: 10.1016/j.jot.2024.08.019

引用次数: 0

Addressing musculoskeletal disorders through new treatment strategies 通过新的治疗策略解决肌肉骨骼疾病问题

IF 5.9 1区医学 Q1 ORTHOPEDICS

Journal of Orthopaedic Translation

Pub Date : 2024-09-01 DOI: 10.1016/j.jot.2024.09.001

引用次数: 0

METTL14-mediated HOXA5 m6A modification alleviates osteoporosis via promoting WNK1 transcription to suppress NLRP3-dependent macrophage pyroptosis METTL14 介导的 HOXA5 m6A 修饰可通过促进 WNK1 转录抑制 NLRP3 依赖性巨噬细胞脓毒症来缓解骨质疏松症

IF 5.9 1区医学 Q1 ORTHOPEDICS

Journal of Orthopaedic Translation

Pub Date : 2024-08-27 DOI: 10.1016/j.jot.2024.08.008

Background

Osteoporosis is a commonly diagnosed metabolic bone disease. NLRP3 inflammasome activation and pyroptosis are observed during osteoporosis. However, the mechanism by which NLRP3-mediated pyroptosis contributes to osteoporosis remains largely undefined.

Methods

Ovariectomized (OVX) mice were employed as an in vivo model of osteoclastogenesis. H&E staining and micro-CT detected the histological changes and bone parameters in the femur tissues. RANKL-treated macrophages were used as the in vitro model of osteoclastogenesis, and LPS/ATP treatment was used as the macrophage pyroptosis model. The cytotoxicity, cytokine secretion and caspase-1 activity were assessed by LDH release assay, ELISA and flow cytometry, respectively. The osteoclast formation ability was detected by TRAP staining. qRT-PCR, IHC and Western blotting detected the expression and localization of METTL14, pyroptosis-related or osteoclast-specific molecules in femur tissues or macrophages. Mechanistically, MeRIP assessed the m⁶A modification of HOXA5. Luciferase and ChIP assays were employed to detect the direct association between HOXA5 and WNK1 promoter in macrophages.

Results

METTL14, HOXA5 and WNK1 were decreased in OVX mice, which was associated with pyroptosis. METTL14 or HOXA5 overexpression suppressed macrophage-osteoclast differentiation and pyroptosis, along with the upregulation of WNK1. METTL14-mediated m⁶A modification stabilized HOXA5 mRNA and increased its expression, and HOXA5 regulated WNK1 expression via direct binding to its promoter. Functional studies showed that WNK1 knockdown counteracted METTL14- or HOXA5-suppressed pyroptosis and macrophage-osteoclast differentiation. In OVX mice, overexpression of METTL14 or HOXA5 alleviated osteoporosis via suppressing WNK1-dependent NLRP3 signaling.

Conclusion

METTL14-mediated HOXA5 m⁶A modification increased its expression, thereby inducing WNK1 expression and suppressing NLRP3-dependent pyroptosis to alleviate osteoporosis. The combination of METTL14 or HOXA5 agonist with pyroptosis targeted therapy may be a promising therapeutic approach for osteoporosis.

The Translational Potential of this Article·

•
METTL14 or HOXA5 overexpression suppressed macrophage-osteoclast differentiation and pyroptosis in macrophages.·
•
METTL14-mediated m6A modification stabilized HOXA5 mRNA and increased its expression.
•
HOXA5 regulated WNK1 expression via direct binding to its promoter.
•
Silencing of WNK1 reversed METTL14- or HOXA5-suppressed pyroptosis and macrophageosteoclast differentiation.·
•
METTL14 or HOXA5 over

背景骨质疏松症是一种常见的代谢性骨病。在骨质疏松症过程中可观察到 NLRP3 炎性体的激活和热蛋白沉积。然而，NLRP3 介导的热蛋白沉积导致骨质疏松症的机制在很大程度上仍未确定。方法采用橘皮切除（OVX）小鼠作为破骨细胞生成的体内模型。H&E染色和显微CT检测了股骨组织的组织学变化和骨参数。RANKL 处理的巨噬细胞被用作破骨细胞生成的体外模型，LPS/ATP 处理的巨噬细胞被用作巨噬细胞热解模型。细胞毒性、细胞因子分泌和 caspase-1 活性分别通过 LDH 释放试验、酶联免疫吸附试验和流式细胞术进行评估。qRT-PCR、IHC和Western blotting检测了METTL14、化脓相关或破骨细胞特异性分子在股骨组织或巨噬细胞中的表达和定位。从机制上讲，MeRIP 评估了 HOXA5 的 m6A 修饰。结果METTL14、HOXA5和WNK1在OVX小鼠中减少，这与脓毒症有关。METTL14或HOXA5的过表达抑制了巨噬细胞-破骨细胞的分化和化脓，同时抑制了WNK1的上调。METTL14介导的m6A修饰稳定了HOXA5 mRNA并增加了其表达，HOXA5通过与其启动子直接结合调控WNK1的表达。功能性研究表明，WNK1的敲除抵消了METTL14或HOXA5抑制的脓毒症和巨噬细胞-破骨细胞分化。结论 METTL14 介导的 HOXA5 m6A 修饰可增加其表达，从而诱导 WNK1 的表达并抑制 NLRP3 依赖性热蛋白沉积，从而缓解骨质疏松症。本文的转化潜力--METTL14或HOXA5的过表达抑制了巨噬细胞-破骨细胞的分化和巨噬细胞的脓毒症--METTL14介导的m6A修饰稳定了HOXA5 mRNA并增加了其表达。--METTL14或HOXA5过度表达可抑制WNK1依赖的NLRP3信号传导，从而缓解OVX小鼠的骨质疏松症。

{"title":"METTL14-mediated HOXA5 m6A modification alleviates osteoporosis via promoting WNK1 transcription to suppress NLRP3-dependent macrophage pyroptosis","authors":"","doi":"10.1016/j.jot.2024.08.008","DOIUrl":"10.1016/j.jot.2024.08.008","url":null,"abstract":"<div><h3>Background</h3><p>Osteoporosis is a commonly diagnosed metabolic bone disease. NLRP3 inflammasome activation and pyroptosis are observed during osteoporosis. However, the mechanism by which NLRP3-mediated pyroptosis contributes to osteoporosis remains largely undefined.</p></div><div><h3>Methods</h3><p>Ovariectomized (OVX) mice were employed as an <em>in vivo</em> model of osteoclastogenesis. H&E staining and micro-CT detected the histological changes and bone parameters in the femur tissues. RANKL-treated macrophages were used as the <em>in vitro</em> model of osteoclastogenesis, and LPS/ATP treatment was used as the macrophage pyroptosis model. The cytotoxicity, cytokine secretion and caspase-1 activity were assessed by LDH release assay, ELISA and flow cytometry, respectively. The osteoclast formation ability was detected by TRAP staining. qRT-PCR, IHC and Western blotting detected the expression and localization of METTL14, pyroptosis-related or osteoclast-specific molecules in femur tissues or macrophages. Mechanistically, MeRIP assessed the m<sup>6</sup>A modification of <em>HOXA5</em>. Luciferase and ChIP assays were employed to detect the direct association between HOXA5 and <em>WNK1</em> promoter in macrophages.</p></div><div><h3>Results</h3><p>METTL14, HOXA5 and WNK1 were decreased in OVX mice, which was associated with pyroptosis. METTL14 or HOXA5 overexpression suppressed macrophage-osteoclast differentiation and pyroptosis, along with the upregulation of WNK1. METTL14-mediated m<sup>6</sup>A modification stabilized <em>HOXA5</em> mRNA and increased its expression, and HOXA5 regulated <em>WNK1</em> expression via direct binding to its promoter. Functional studies showed that WNK1 knockdown counteracted METTL14- or HOXA5-suppressed pyroptosis and macrophage-osteoclast differentiation. In OVX mice, overexpression of METTL14 or HOXA5 alleviated osteoporosis via suppressing WNK1-dependent NLRP3 signaling.</p></div><div><h3>Conclusion</h3><p>METTL14-mediated <em>HOXA5</em> m<sup>6</sup>A modification increased its expression, thereby inducing <em>WNK1</em> expression and suppressing NLRP3-dependent pyroptosis to alleviate osteoporosis. The combination of METTL14 or HOXA5 agonist with pyroptosis targeted therapy may be a promising therapeutic approach for osteoporosis.</p></div><div><h3>The Translational Potential of this Article·</h3><p></p><ul><li><span>•</span><span><p>METTL14 or HOXA5 overexpression suppressed macrophage-osteoclast differentiation and pyroptosis in macrophages.·</p></span></li><li><span>•</span><span><p>METTL14-mediated m6A modification stabilized HOXA5 mRNA and increased its expression.</p></span></li><li><span>•</span><span><p>HOXA5 regulated WNK1 expression via direct binding to its promoter.</p></span></li><li><span>•</span><span><p>Silencing of WNK1 reversed METTL14- or HOXA5-suppressed pyroptosis and macrophageosteoclast differentiation.·</p></span></li><li><span>•</span><span><p>METTL14 or HOXA5 over","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214031X24000950/pdfft?md5=7eb5c8164c8519c68ffa80f040877e93&pid=1-s2.0-S2214031X24000950-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142076678","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

Memantine attenuates the development of osteoarthritis by blocking NMDA receptor mediated calcium overload and chondrocyte senescence 美金刚烷通过阻断 NMDA 受体介导的钙超载和软骨细胞衰老来减轻骨关节炎的发展

IF 5.9 1区医学 Q1 ORTHOPEDICS

Journal of Orthopaedic Translation

Pub Date : 2024-08-27 DOI: 10.1016/j.jot.2024.08.007

Background

Memantine, which is an FDA-proven drug for the treatment of dementia, exerts its function by blocking the function of NMDA (N-methyl-D-aspartate) receptor, a calcium-permeable ion channel that reduces cytotoxic calcium overload. Chondrocyte senescence is a crucial cellular event that contributes to articular cartilage degeneration during osteoarthritis (OA) development. To date, the effects of memantine and its downstream NMDA receptor on chondrocyte senescence and OA have been rarely reported.

Methods

The protein levels of NMDA receptor and its agonistic ligand, glutamate, were compared between normal and OA chondrocytes. The quantity of intracellular calcium ions and the level of mitochondrial damage were evaluated using specific fluorescent probes and transmission electron microscopy (TEM), respectively. Chondrocyte senescence was evaluated by senescence-associated β-galactosidase (SA-β-Gal) staining and p16^INK4a analysis. The function of NMDA receptor in chondrocyte senescence and OA was tested via agonists activation and gene knockdown experiments. The therapeutic effects of memantine on OA were examined both in vitro and in vivo. Additionally, to verify the findings from animal samples, a propensity score-matched cohort study was conducted using data from a United Kingdom primary care database (i.e., IQVIA Medical Research Database [IMRD]) to compare the risk of OA-related joint replacement involved in memantine initiators versus active comparators (i.e., acetylcholinesterase [AchE] initiators) in patients with dementia.

Results

The protein expression of NMDA receptor and the secretion of glutamate were both significantly increased in OA chondrocytes. NMDA receptor activation was found to stimulate chondrocyte calcium overload, which further led to mitochondrial fragmentation and chondrocyte senescence. Blocking the NMDA receptor with memantine and N-methyl-D-aspartate receptor subunit 1(NR1, the gene encoding NMDA receptor) knockdown resulted in reduced calcium influx, mitochondrial fragmentation, as well as cellular senescence in OA chondrocytes. Intra-articular injection of memantine in OA mice also exhibited protective effects against cartilage degeneration. Moreover, in the 1:5 propensity score-matched cohort study consisting of 6218 patients (n = 1435 in the memantine cohort; n = 4783 in the AchE cohort), the memantine initiator was associated with a lower risk of OA-related joint replacement than AchE initiators (Hazard ratio = 0.56, 95 % confidence interval: 0.34 to 0.99).

Conclusion

NMDA receptor plays an important role in inflammatory-induced cytotoxic calcium overload in chondrocytes, while memantine can effectively block the NMDA receptor to reduce chondrocyte senescence and retard the development of OA.

The translational potential of this article

As a clinically licensed dru

背景美金刚是美国食品与药物管理局批准用于治疗痴呆症的药物，它通过阻断NMDA（N-甲基-D-天冬氨酸）受体的功能发挥其作用，NMDA受体是一种钙离子通道，可减少细胞毒性钙超载。软骨细胞衰老是骨关节炎（OA）发展过程中导致关节软骨退化的关键细胞事件。迄今为止，美金刚及其下游 NMDA 受体对软骨细胞衰老和 OA 的影响还鲜有报道。方法比较正常软骨细胞和 OA 软骨细胞中 NMDA 受体及其激动配体谷氨酸的蛋白水平。分别使用特异性荧光探针和透射电子显微镜（TEM）评估细胞内钙离子的数量和线粒体损伤的程度。通过衰老相关的β-半乳糖苷酶（SA-β-Gal）染色和p16INK4a分析评估了软骨细胞的衰老。通过激动剂激活和基因敲除实验检测了NMDA受体在软骨细胞衰老和OA中的功能。在体外和体内研究了美金刚对 OA 的治疗效果。此外，为了验证动物样本的研究结果，还利用英国初级保健数据库（即 IQVIA 医学研究数据库 [IMRD]）中的数据进行了倾向得分匹配队列研究，以比较美金刚启动者与活性比较者（即：美金刚启动者和美金刚活性比较者）发生与 OA 相关的关节置换的风险、结果在 OA 软骨细胞中，NMDA 受体的蛋白表达和谷氨酸的分泌均显著增加。研究发现，NMDA 受体激活可刺激软骨细胞钙超载，从而进一步导致线粒体破碎和软骨细胞衰老。用美金刚和N-甲基-D-天冬氨酸受体亚单位1（NR1，编码NMDA受体的基因）敲除阻断NMDA受体可减少钙离子流入、线粒体破碎以及OA软骨细胞的细胞衰老。在 OA 小鼠的关节内注射美金刚也能对软骨退化起到保护作用。此外，在由 6218 名患者组成的 1:5 倾向得分匹配队列研究中（美金刚队列中的人数为 1435 人；AchE 队列中的人数为 4783 人），与 AchE 队列中的人数相比，美金刚启动者发生与 OA 相关的关节置换的风险较低（危险比为 0.56，95 % 置信区间：0.34 至 0.99）。结论NMDA受体在炎症诱导的软骨细胞细胞毒性钙超载中起着重要作用，而美金刚能有效阻断NMDA受体，减少软骨细胞衰老，延缓OA的发展。从机理上讲，美金刚是通过阻断NMDA受体介导软骨细胞衰老而发挥作用的。美金刚对 OA 的保护作用不仅通过体内和体外实验得到了验证，还通过倾向得分匹配人类队列研究得到了验证。这些发现为美金刚治疗 OA 提供了强有力的证据。

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引用次数: 0

Advanced therapy with mesenchymal stromal cells for knee osteoarthritis: Systematic review and meta-analysis of randomized controlled trials 间充质基质细胞治疗膝骨关节炎的先进疗法：随机对照试验的系统回顾和荟萃分析

IF 5.9 1区医学 Q1 ORTHOPEDICS

Journal of Orthopaedic Translation

Pub Date : 2024-08-26 DOI: 10.1016/j.jot.2024.07.012

Background

Advanced cell therapies emerged as promising candidates for treatment of knee articular diseases, but robust evidence regarding their clinical applicability is still lacking.

Objective

To assess the efficacy and safety of advanced mesenchymal stromal cells (MSC) therapy for knee osteoarthritis (OA) and chondral lesions.

Methods

Systematic review of randomized controlled trials conducted in accordance with Cochrane Handbook and reported following PRISMA checklist. GRADE approach was used for assessing the evidence certainty.

Results

25 randomized controlled trials that enrolled 1048 participants were included. Meta-analyses data showed that, compared to viscosupplementation (VS), advanced MSC therapy resulted in a 1.91 lower pain VAS score (95 % CI ‐3.23 to −0.59; p < 0.00001) for the treatment of knee OA after 12 months. Compared to placebo, the difference was 0.99 lower pain VAS points (95 % CI ‐1.94 to −0.03; p = 0.76). According to the GRADE approach, the evidence was very uncertain for both comparisons. By excluding studies with high risk of bias, there was a similar size of effect (VAS MD ‐1.54, 95 % CI ‐2.09 to −0.98; p = 0.70) with improved (moderate) certainty of evidence, suggesting that MSC therapy probably reduces pain slightly better than VS. Regarding serious adverse events, there was no difference from advanced MSC therapy to placebo or to VS, with very uncertain evidence.

Conclusion

Advanced MSC therapy resulted in lower pain compared to placebo or VS for the treatment of knee OA after 12 months, with no difference in adverse events. However, the evidence was considered uncertain.

The Translational Potential of this Article

Currently, there is a lack of studies with good methodological structure aiming to evaluate the real clinical impact of advanced cell therapy for knee OA. The present study was well structured and conducted, with Risk of Bias, GRADE certainty assessment and sensitivity analysis. It explores the translational aspect of the benefits and safety of MSC compared with placebo and gold-standard therapy to give practitioners and researchers support to expand this therapy in their practice.

PROSPERO registration number

CRD42020158173. Access at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=158173.

背景先进的细胞疗法成为治疗膝关节疾病的有前途的候选疗法，但仍缺乏有关其临床适用性的有力证据。目的评估先进间充质干细胞（MSC）疗法治疗膝关节骨关节炎（OA）和软骨损伤的有效性和安全性。方法根据《Cochrane手册》对随机对照试验进行系统综述，并按照PRISMA清单进行报告。结果纳入了 25 项随机对照试验，共 1048 人参与。元分析数据显示，与粘液补充剂（VS）相比，高级间充质干细胞疗法治疗膝关节 OA 12 个月后，疼痛 VAS 评分降低了 1.91（95 % CI -3.23 至 -0.59；p <0.00001）。与安慰剂相比，疼痛VAS评分降低了0.99分（95 % CI -1.94至-0.03；p = 0.76）。根据 GRADE 方法，这两项比较的证据都很不确定。排除偏倚风险较高的研究后，效果大小相似（VAS MD -1.54, 95 % CI -2.09 to -0.98；p = 0.70），证据确定性有所提高（中度），表明间充质干细胞疗法减轻疼痛的效果可能略优于VS。在严重不良事件方面，高级间充质干细胞疗法与安慰剂或VS相比没有差异，证据非常不确定。结论在治疗膝关节OA 12个月后，高级间充质干细胞疗法与安慰剂或VS相比可降低疼痛，在不良事件方面没有差异。本文的转化潜力目前，还缺乏具有良好方法学结构的研究来评估高级细胞疗法对膝关节OA的真正临床影响。本研究结构严谨、方法得当，并进行了偏倚风险、GRADE确定性评估和敏感性分析。它从转化的角度探讨了间充质干细胞与安慰剂和黄金标准疗法相比的益处和安全性，为从业人员和研究人员在实践中推广这种疗法提供了支持。PROSPERO注册号为CRD42020158173。请访问 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=158173。

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引用次数: 0

Diagnosis and treatment of anterior cruciate ligament injuries: Consensus of Chinese experts part II: Graft selection and clinical outcome evaluation 前十字韧带损伤的诊断和治疗：中国专家共识第二部分：移植物选择和临床效果评估

IF 5.9 1区医学 Q1 ORTHOPEDICS

Journal of Orthopaedic Translation

Pub Date : 2024-08-23 DOI: 10.1016/j.jot.2024.07.002

Background

In the recent decade, there has been substantial progress in the technologies and philosophies associated with diagnosing and treating anterior cruciate ligament (ACL) injuries in China. The therapeutic efficacy of ACL reconstruction in re-establishing the stability of the knee joint has garnered widespread acknowledgment. However, the path toward standardizing diagnostic and treatment protocols remains to be further developed and refined.

Objective

In this context, the Chinese Association of Orthopaedic Surgeons (CAOS) and the Chinese Society of Sports Medicine (CSSM) collaboratively developed an expert consensus on diagnosing and treating ACL injury, aiming to enhance medical quality through refining professional standards.

Methods

The consensus drafting team invited experts across the Greater China region, including the mainland, Hong Kong, Macau, and Taiwan, to formulate and review the consensus using a modified Delphi method as a standardization approach. As members of the CSSM Lower Limb Study Group and the CAOS Arthroscopy and Sports Medicine Study Group, invited experts concentrated on two pivotal issues: “Graft Selection” and “Clinical Outcome Evaluation” during the second part of the consensus development.

Results

This focused discussion ultimately led to a strong consensus on nine specific consensus terms.

Conclusion

The consensus clearly states that ACL reconstruction has no definitive “gold standard” graft choice. Autografts have advantages in healing capability but are limited in availability and have potential donor site morbidities; allografts reduce surgical trauma but incur additional costs, and there are concerns about slow healing, quality control issues, and a higher failure rate in young athletes; synthetic ligaments allow for early rehabilitation and fast return to sport, but the surgery is technically demanding and incurs additional costs. When choosing a graft, one should comprehensively consider the graft's characteristics, the doctor's technical ability, and the patient's needs. When evaluating clinical outcomes, it is essential to ensure an adequate sample size and follow-up rate, and the research should include patient subjective scoring, joint function and stability, complications, surgical failure, and the return to sport results. Medium and long-term follow-ups should not overlook the assessment of knee osteoarthritis.

背景近十年来，中国在诊断和治疗前交叉韧带（ACL）损伤的相关技术和理念方面取得了长足的进步。前交叉韧带重建在重建膝关节稳定性方面的疗效已得到广泛认可。在此背景下，中华医学会骨科分会和中华医学会运动医学分会共同制定了《前交叉韧带损伤诊治专家共识》，旨在通过细化专业标准提高医疗质量。方法：共识起草小组邀请了大中华地区（包括大陆、香港、澳门和台湾）的专家，采用改良德尔菲法作为标准化方法，制定并审查共识。作为 CSSM 下肢研究小组和 CAOS 关节镜与运动医学研究小组的成员，受邀专家集中讨论了两个关键问题："结论该共识明确指出，前交叉韧带重建没有明确的 "金标准 "移植物选择。自体移植物在愈合能力方面具有优势，但其可用性有限，且存在潜在的供体部位病变；同种异体移植物可减少手术创伤，但会产生额外费用，且存在愈合缓慢、质量控制问题以及年轻运动员失败率较高等问题；合成韧带可实现早期康复和快速恢复运动，但手术技术要求高且会产生额外费用。在选择移植物时，应综合考虑移植物的特性、医生的技术能力和患者的需求。在评估临床疗效时，必须确保足够的样本量和随访率，研究内容应包括患者主观评分、关节功能和稳定性、并发症、手术失败、恢复运动效果等。中长期随访不应忽视对膝关节骨关节炎的评估。

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