Osteoarthritis and Cartilage最新文献_第4页

M2 macrophages regulate nucleus pulposus cell extracellular matrix synthesis through the OPN-CD44 axis in intervertebral disc degeneration.

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-01-20 DOI: 10.1016/j.joca.2024.12.007

Zhiwen Tao, Tianyou Zhang, Yaning Ge, Lingzhi Li, Cheng Ma, Zhengbo Wang, Tong Chen, Helong Zhang, Ruya Li, Tao Jiang, Yongxin Ren

Objective: Macrophages play a crucial role in various physiological processes. In intervertebral disc degeneration (IDD), macrophage infiltration has been observed in human intervertebral disc (IVD) specimens, but how macrophages influence IDD remains unclear.

Methods: According to the single-cell transcriptome expression profiles from GSE165722, we verified the infiltration of macrophages in IDD and the possible interaction between infiltrated macrophages and nucleus pulposus cells (NPCs). The expression of macrophage-associated markers was verified in specimens of human nucleus pulposus, lumbar spinal instability mice and annulus fibrosus puncture mice. By treating NPCs cocultured with M2 macrophages with osteopontin (OPN) neutralization antibody and siCD44, we demonstrated that both in vitro and in vivo macrophages regulated IDD through the OPN-CD44 axis. Using transforming growth factor beta 1 and siCD44 treatment, we verified that CD44 regulated the pSMAD2/3 pathway.

Results: IDD engaged macrophage infiltration, mainly gathered in the endplate, and induced macrophage M2 polarization. Infiltrated macrophages showed high-level expression of OPN, and NPCs showed upregulated CD44. Depletion of macrophages significantly decreased the expression of OPN and CD44 in degenerative IVD, concurrently exacerbating IDD. The co-culture of macrophages and NPCs in vitro demonstrated that the conditioned media from NPCs induced macrophage M2 polarization. Further, M2 macrophages rescued NPCs extracellular matrix (ECM) phenotype through the OPN-CD44 axis, by regulating pSMAD2/3 nuclear translocation.

Conclusions: Our findings suggest that macrophages regulate NPC ECM expression in IDD through the OPN-CD44 axis, emphasizing the therapeutic potential of targeting macrophages and the OPN-CD44 axis for IDD prevention and treatment.

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引用次数: 0

Role of mitophagy in intervertebral disc degeneration: A narrative review 有丝分裂在椎间盘退化中的作用：叙述性综述。

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-01-01 DOI: 10.1016/j.joca.2024.09.013

Zuo-long Wu , Yong Liu , Wei Song , Kai-sheng Zhou , Yan Ling , Hai-hong Zhang

Objective

The pivotal role of mitophagy in the initiation and progression of intervertebral disc (IVD) degeneration (IDD) has become increasingly apparent due to a growing body of research on its pathogenesis. This review summarizes the role of mitophagy in IDD and the therapeutic potential of targeting this process.

Design

This narrative review is divided into three parts: the regulatory mechanisms of mitophagy, the role of mitophagy in IDD, and the applications and prospects of mitophagy for the treatment of IDD.

Results

Mitophagy protects cells against harmful external stimuli and plays a crucial protective role by promoting extracellular matrix (ECM) production, inhibiting ECM degradation, and reducing apoptosis, senescence, and cartilage endplate calcification. However, excessive mitophagy is often detrimental to cells. Currently, the regulatory mechanisms governing appropriate and excessive mitophagy remain unclear.

Conclusions

Proper mitophagy effectively maintains IVD cell homeostasis and slows the progression of IDD. Conversely, excessive mitophagy may accelerate IDD development. Further research is needed to elucidate the regulatory mechanisms underlying appropriate and excessive mitophagy, which could provide new theoretical support for the application of mitophagy targeting to the treatment of IDD.

目的：随着对椎间盘（IVD）变性（IDD）发病机制研究的不断深入，有丝分裂在椎间盘（IVD）变性的发生和发展过程中的关键作用日益明显。本综述总结了有丝分裂在IDD中的作用以及针对这一过程的治疗潜力：本综述分为三个部分：有丝分裂的调控机制、有丝分裂在IDD中的作用以及有丝分裂在IDD治疗中的应用和前景：有丝分裂能保护细胞免受外界有害刺激，并通过促进细胞外基质（ECM）生成、抑制ECM降解、减少细胞凋亡、衰老和软骨终板钙化发挥重要的保护作用。然而，过度的有丝分裂往往对细胞有害。目前，适当和过度有丝分裂的调控机制仍不清楚：结论：适当的有丝分裂能有效维持 IVD 细胞的平衡并减缓 IDD 的进展。相反，过度的有丝分裂可能会加速 IDD 的发展。需要进一步研究阐明适当和过度有丝分裂的调控机制，这将为有丝分裂靶向治疗IDD提供新的理论支持。

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引用次数: 0

H3K9me3 loss and ERVs activation as hallmarks for osteoarthritis progression and knee joint aging H3K9me3 缺失和 ERV 激活是骨关节炎进展和膝关节老化的标志。

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-01-01 DOI: 10.1016/j.joca.2024.08.004

Ye Liu , Vladimir Molchanov , Yaguang Zhao , Di Lu , Huadie Liu , H. Josh Jang , Tao Yang

Objective

This study aims to link aberrant endogenous retroviruses (ERVs) activation and osteoarthritis (OA) progression by comparing the chromatin accessibility and transcriptomic landscapes of diseased or intact joint tissues of OA patients.

Method

We performed ERVs-centric analysis on published ATAC-seq and RNA-seq data from OA patients’ cartilage tissues. Here, we compared the outer region of the lateral tibial plateau, representing intact cartilage, to the inner region of the medial tibial plateau, representing damaged cartilage. In addition, cartilage tissue sections from OA patients and post-traumatic OA mouse models were assayed for global H3K9me3 abundance through immunohistochemistry staining.

Results

Chromatin accessibility and transcription of ERVs, particularly from evolutionarily "intermediate age" ERVs families (ERV1 and ERVL), were enriched and elevated in OA cartilage. This integrative analysis suggests that H3K9me3-related heterochromatin loss might be mechanistically connected to ERV activation in OA tissue. We further verified that global H3K9me3 levels were reduced in diseased cartilage relative to intact tissue in OA patients and injury-induced OA mice.

Conclusion

The findings suggest a compelling hypothesis that the loss of H3K9me3, either due to aging or cellular stressors, may lead to ERVs reactivation that contributes to tissue inflammation and OA progression. This study unveils the intricate relationship between epigenetic alterations, ERVs activation, and OA, paving the way for potential therapeutic interventions targeting these pathogenic mechanisms.

研究目的本研究旨在通过比较 OA 患者病变或完整关节组织的染色质可及性和转录组景观，将异常内源性逆转录病毒（ERV）激活与骨关节炎（OA）进展联系起来：我们对已发表的OA患者软骨组织的ATAC-seq和RNA-seq数据进行了以ERV为中心的分析。在这里，我们比较了代表完整软骨的胫骨外侧平台外侧区域（oLT）和代表受损软骨的胫骨内侧平台内侧区域（iMT）。此外，还通过免疫组化（IHC）染色法检测了OA患者和创伤后OA小鼠模型的软骨组织切片的H3K9me3丰度：结果：在OA软骨中，ERV的染色质可及性和转录，特别是来自进化 "中年 "ERV家族（ERV1和ERVL）的ERV，被富集和升高。这一综合分析表明，H3K9me3相关异染色质的缺失可能与OA组织中ERV的激活存在机理上的联系。我们进一步证实，相对于OA患者和损伤诱导的OA小鼠的完整组织，病变软骨中的整体H3K9me3水平降低了：研究结果提出了一个令人信服的假设，即由于衰老或细胞应激因素导致的H3K9me3损失可能会导致ERV重新激活，从而导致组织炎症和OA进展。这项研究揭示了表观遗传学改变、ERV 激活和 OA 之间错综复杂的关系，为针对这些致病机制的潜在治疗干预铺平了道路。

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引用次数: 0

Antihistamine use and osteoarthritis or joint pain 使用抗组胺药和骨关节炎或关节疼痛

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-01-01 DOI: 10.1016/j.joca.2024.09.004

Aleksandra Turkiewicz, Clara Hellberg, Andrea Dell’Isola , Martin Englund

Objectives

Antihistamines have been reported to be linked with less pain in osteoarthritis. We aimed to estimate associations between antihistamine use and three outcomes: prevalent osteoarthritis, current joint pain, and developing osteoarthritis.

Methods

We included 25 003 participants of EpiHealth – a cohort of persons aged 45 to 75 from Malmö/Uppsala in Sweden. Participants self-reported the presence of allergy, joint pain and osteoarthritis at a study visit between years 2010 and 2016. Further, we obtained data about diagnoses of allergy and osteoarthritis from health-care registers (primary, specialist and inpatient care). Exposure was prescribed dispensed antihistamines (H1-antagonists) during ∼6 years preceding the EpiHealth visit retrieved from the Prescribed Drugs Register. The outcomes were osteoarthritis (any location), pain in knees/hips/hands-wrists at the examination (cross-sectional) and future incident diagnosis of osteoarthritis (longitudinal, in a cohort free of osteoarthritis at EpiHealth). We report risk ratios (95% confidence intervals [CI]) from logistic regression and hazard ratios (HR) from Cox regression, from models adjusted for age, sex, body mass index, allergy and use of healthcare. We used prescribed dispensed penicillin as negative control.

Results

The associations between use of antihistamines and osteoarthritis/joint pain at EpiHealth were 1.13 (95%CI 1.06, 1.20) and 1.02 (0.99, 1.05), respectively. The HR of future incident osteoarthritis diagnosis with use of antihistamines was 1.15 (1.03, 1.28). The association (HR) between penicillin use and future incident osteoarthritis diagnosis was 1.16 (1.07, 1.25).

Conclusions

In a large population-based observational cohort, use of antihistamines was neither associated with less joint pain/osteoarthritis nor lower risk of future osteoarthritis.

据报道，抗组胺药物可减轻骨关节炎患者的疼痛。我们的目的是估算抗组胺药的使用与以下三种结果之间的关系：骨关节炎的发病率、当前的关节疼痛以及骨关节炎的发展。

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引用次数: 0

Association of dorsal malunion in distal radius fractures with wrist osteoarthritis: Alterations of bone density and stress-distribution patterns in relation to deformation angles 桡骨远端骨折背侧错位与腕关节骨关节炎的关系：骨密度和应力分布模式的改变与变形角度的关系。

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-01-01 DOI: 10.1016/j.joca.2024.08.006

Arisa Kazui , Satoshi Miyamura , Ryoya Shiode , Natsuki Yamamoto , Tasuku Miyake , Toru Iwahashi , Hiroyuki Tanaka , Seiji Okada , Tsuyoshi Murase , Kunihiro Oka

Objective

Distal radius fractures (DRFs) with dorsal malunion increase the risk of osteoarthritis (OA), although the cause of post-DRF OA is yet to be elucidated. To clarify the abnormal effects of a post-DRF dorsal radius deformity, we evaluated the bone density (BD) and stress-distribution patterns of the articular surface in dorsally malunited DRFs.

Design

In 36 cases of dorsally malunited DRFs following extra-articular fractures, we generated three-dimensional computerized models of the malunited distal radius from computed tomography data and extracted the subchondral bones of the radiocarpal joint (RCJ) and distal radioulnar joint (DRUJ). Both BD and stress distribution in the subchondral bones were quantitatively evaluated by comparing the affected and normal sides. Correlations of alterations in high-BD distribution and deformation angles were analyzed.

Results

The center of high-BD distribution from the center of the RCJ in the volar(-)-dorsal(+) direction was dorsal (0.56 ± 0.72 mm) on the affected side compared with the normal side (−0.15 ± 0.63 mm) [95% CI: 0.43, 1.00, P < 0.0001]. The maximum stress distribution was also dorsal on the affected side (2.34 ± 3.52 mm) compared with the normal side (−2.49 ± 1.62 mm) [95% CI: 0.89, 1.79, P < 0.0001]. The alterations in BD and stress distribution correlated with the dorsiflexion and radial deviation angles. In the DRUJ, there was no significant difference in BD between the affected and normal sides.

Conclusions

In dorsally malunited DRFs, the alignment change of the RCJ resulted in high BD-concentration areas and stress distribution on the dorsal side of the radius, which may constitute a precursor for OA.

目的：桡骨远端骨折（DRF）伴有背侧畸形会增加骨关节炎（OA）的风险，但桡骨远端骨折后OA的病因尚未阐明。为了明确DRF后桡骨背侧畸形的异常影响，我们评估了背侧畸形DRF关节面的骨密度（BD）和应力分布模式：在36例关节外骨折后背侧畸形的DRF中，我们通过计算机断层扫描数据生成了畸形桡骨远端三维计算机模型，并提取了桡腕关节（RCJ）和桡尺关节远端（DRUJ）的软骨下骨。通过比较患侧和正常侧，对软骨下骨的BD和应力分布进行了定量评估。分析了高BD分布变化与变形角度的相关性：结果：与正常侧（-0.15±0.63 mm）[95% CI: 0.43, 1.00, PConclusions：在背侧畸形的DRF中，RCJ的排列变化导致桡骨背侧出现高BD集中区和应力分布，这可能是OA的前兆。

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引用次数: 0

Osteoarthritis Year in Review 2024: Molecular biomarkers of osteoarthritis 骨关节炎 2024 年回顾：骨关节炎的分子生物标志物。

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-01-01 DOI: 10.1016/j.joca.2024.10.003

Hope D. Welhaven , Avery H. Welfley , Ronald K. June

Objective

To provide a comprehensive and insightful summary of studies on molecular biomarkers at the gene, protein, and metabolite levels across different sample types and joints affected by osteoarthritis (OA).

Methods

A literature search using the PubMed database for publications on OA biomarkers published between April 1, 2023 and April 30, 2024 was performed. Publications were then screened, examined at length, and summarized in a narrative review.

Results

Out of the 364 papers initially identified, 44 publications met inclusion criteria, were relevant to OA, and were further examined for data extraction and discussion. These studies included 1 genomic analysis, 22 on protein markers, 6 on metabolite markers, 9 on inflammatory mediators, and 6 integrating multiple molecular levels.

Conclusions

Significant advancements have been made in identifying molecular biomarkers for OA, encompassing various joints, sample types, and molecular levels. Despite this progress, gaps remain, particularly in the need for validation, larger sample sizes, the integration of more clinical data, and consideration of covariates. For early detection and improved treatment of OA, continued efforts in biomarker identification are needed. This effort should seek to identify effective biomarkers that advance early detection, support prevention, evaluate interventions, and improve patient outcomes.

目的方法：使用PubMed数据库对2023年4月1日至2024年4月30日期间发表的有关OA生物标志物的文献进行检索：方法：使用 PubMed 数据库检索 2023 年 4 月 1 日至 2024 年 4 月 30 日期间发表的有关 OA 生物标志物的文献。结果：在最初确定的 364 篇论文中，有 6 篇发表于 2023 年 4 月 1 日至 2024 年 4 月 30 日之间：在初步确定的 364 篇论文中，有 44 篇符合纳入标准，与 OA 相关，并进一步进行了数据提取和讨论。这些研究包括 1 项基因组分析、22 项蛋白质标记物研究、6 项代谢物标记物研究、9 项炎症介质研究和 6 项综合多个分子水平的研究：在鉴定 OA 分子生物标志物方面取得了重大进展，包括不同关节、样本类型和分子水平。尽管取得了这些进展，但差距依然存在，特别是需要验证、扩大样本量、整合更多临床数据以及考虑协变量。为了及早发现并改善对 OA 的治疗，需要继续努力进行生物标志物鉴定。这项工作应寻求确定有效的生物标志物，以促进早期检测、支持预防、评估干预措施并改善患者预后。

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引用次数: 0

Response to letter to the editor regarding ‘Association between synovial tissue damage and pain in late-stage knee osteoarthritis: A cross-sectional study’ 对 "膝关节骨性关节炎晚期滑膜组织损伤与疼痛之间的关系：一项横断面研究 "的致编辑信的回复。

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-01-01 DOI: 10.1016/j.joca.2024.10.012

Holly T. Philpott , Trevor B. Birmingham , C. Thomas Appleton , On behalf of the WOREO Knee Study Group

引用次数: 0

When ‘synovitis’ is not synovitis 当 "滑膜炎 "不是滑膜炎时

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-01-01 DOI: 10.1016/j.joca.2024.09.005

Sung Yeon Kim , Carla R. Scanzello

引用次数: 0

Longitudinal stability of molecular endotypes of knee osteoarthritis patients 膝关节骨关节炎患者分子内型的纵向稳定性。

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-01-01 DOI: 10.1016/j.joca.2024.11.002

Monica T. Hannani , Christian S. Thudium , Alfred C. Gellhorn , Jonathan Larkin , Morten A. Karsdal , Zofia Lisowska-Petersen , Peder Frederiksen , Cecilie L. Bager , Christoph Ladel , André Struglics , Melanie Uebelhoer , Yves Henrotin , Asger R. Bihlet , Francisco J. Blanco , Ida K. Haugen , Margreet Kloppenburg , Francis Berenbaum , Ali Mobasheri , Jaume Bacardit , Anne-Christine Bay-Jensen

Objective

To assess the longitudinal stability of biomarker-based molecular endotypes of knee osteoarthritis (KOA) participants from APPROACH and to evaluate the consistency of findings in an independent KOA population.

Methods

Nineteen biomarkers were measured longitudinally in 295 KOA participants from the APPROACH cohort. K-means clustering was used to identify the structural damage, inflammation, and low tissue turnover endotypes at the six-, 12-, and 24-month follow-ups. Endotype stability was defined as having the same independent endotype assignment longitudinally for patients with complete data (n = 226). Clinical and biochemical characteristics were compared between participants with longitudinally stable and unstable endotypes. The presence and longitudinal stability of the endotypes were evaluated in a different KOA population from the placebo arm of the oral salmon calcitonin trials.

Results

An average overall longitudinal endotype stability of 55% (Fleiss’ Kappa of 0.53; 95% confidence interval [CI]: 0.46, 0.60) was demonstrated. An average stability of 59% (range: 54–59%) was observed for the structural damage endotype (Fleiss’ Kappa 0.52; 95% CI: 0.45, 0.60), 54% (52–56%) for the inflammatory (Fleiss’ Kappa 0.61; 95% CI: 0.53, 0.68), and 50% (49–52%) for the low tissue turnover endotype (Fleiss’ Kappa 0.46; 95% CI: 0.39, 0.54). Participants with longitudinally unstable endotypes exhibited molecular properties of more than one endotype, which were detectable already at the first visit.

Conclusions

Our study showed for the first time that more than half of KOA participants exhibited a longitudinally stable endotype, highlighting the applicability of biomarker-based endotyping in a clinical trial setting.

目的评估 APPROACH 中膝关节骨性关节炎（KOA）患者基于生物标志物的分子内型的纵向稳定性，并评估在一个独立的 KOA 群体中研究结果的一致性：方法：对来自 APPROACH 队列的 295 名 KOA 患者的 19 种生物标记物进行了纵向测量。在6个月、12个月和24个月的随访中，采用K均值聚类方法确定结构损伤、炎症和低组织周转内型。对于数据完整的患者（n = 226），内型稳定性的定义是纵向具有相同的独立内型分配。比较了内型纵向稳定和不稳定患者的临床和生化特征。在口服鲑鱼降钙素试验安慰剂组的不同KOA人群中，对内型的存在和纵向稳定性进行了评估：结果：平均总体纵向内型稳定性为 55%（Fleiss' Kappa 为 0.53；95% CI：0.46, 0.60）。结构损伤内型的平均稳定性为 59%（范围：54% - 59%）（Fleiss' Kappa 0.52；95% CI：0.45, 0.60），炎症内型的平均稳定性为 54%（52% - 56%）（Fleiss' Kappa 0.61；95% CI：0.53, 0.68），低组织周转内型的平均稳定性为 50%（49% - 52%）（Fleiss' Kappa 0.46；95% CI：0.39, 0.54）。纵向内型不稳定的参与者表现出不止一种内型的分子特性，在首次就诊时就能检测到：我们的研究首次表明，半数以上的 KOA 参与者表现出纵向稳定的内型，这凸显了基于生物标志物的内型分析在临床试验中的适用性。

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引用次数: 0

Osteoarthritis year in review 2024: Genetics, genomics, and epigenetics 骨关节炎 2024 年回顾：遗传学、基因组学和表观遗传学。

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2025-01-01 DOI: 10.1016/j.joca.2024.10.014

Cindy G. Boer

Objective

The purpose of this narrative review is to highlight the advances made in the past 12 months in the field of osteoarthritis genetics, genomics and epigenetics.

Methods

The Medline and Embase databases were systematically searched for original publications using terminology, and combinations of terminology, relating to: “osteoarthritis”, “genetics”, “genomics”, and “epigenetics”. Only original research articles published in the English language between the OARSI congresses of April 2032 and April 2024 were considered.

Results

This narrative review focuses only on studies using genome-wide omics techniques in human material. There was a rise in functional genomics studies across different osteoarthritis-relevant tissues, which have robustly identified an additional 26 genes involved in osteoarthritis pathology. Two of such previously identified genes (MGP, ALDH1A2) are currently the target of ongoing clinical trials for osteoarthritis. This past year also saw the use of single-cell transcriptomics and two relatively new omics: epitranscriptomics and mitochondrial genomics.

Conclusion

This past year of genomics research has led to multiple exciting findings involving genes and mechanisms linked to osteoarthritis. Moreover, the comprehensive genome-wide omics datasets generated for diverse osteoarthritis tissues will prove invaluable for future research aimed at elucidating more causal biological mechanisms and possible therapeutic targets for osteoarthritis.

摘要这篇叙述性综述旨在强调过去 12 个月中在骨关节炎遗传学、基因组学和表观遗传学领域取得的进展：方法：在 Medline 和 Embase 数据库中系统地检索了与以下方面相关的术语和术语组合的原始出版物："骨关节炎"、"遗传学"、"基因组学 "和 "表观遗传学"。只有在 2032 年 4 月至 2024 年 4 月 OARSI 大会期间用英语发表的原创研究文章才会被考虑：本综述只关注在人体材料中使用全基因组 omics 技术的研究。对不同骨关节炎相关组织的功能基因组学研究有所增加，这些研究有力地确定了另外 26 个参与骨关节炎病理的基因。其中两个先前发现的基因（MGP、ALDH1A2）目前是正在进行的骨关节炎临床试验的目标基因。在过去的一年里，还出现了单细胞转录组学和两种相对较新的 omics：表转录组学和线粒体基因组学：结论：过去一年的基因组学研究取得了多项令人振奋的发现，涉及与骨关节炎相关的基因和机制。此外，针对不同骨关节炎组织生成的全基因组 omics 数据集对于今后旨在阐明骨关节炎的更多因果生物机制和可能的治疗靶点的研究将证明是非常有价值的。

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引用次数: 0