Osteoarthritis and Cartilage最新文献

英文中文

A standardized approach to evaluation and reporting of synovial histopathology in two surgically induced murine models of osteoarthritis 在两种手术诱导的骨关节炎小鼠模型中评估和报告滑膜组织病理学的标准化方法。

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2024-05-31 DOI: 10.1016/j.joca.2024.05.006

Objective

Synovial pathology has been linked to osteoarthritis (OA) pain in patients. Microscopic grading systems for synovial changes in human OA have been described, but a standardized approach for murine models of OA is needed. We sought to develop a reproducible approach and set of minimum recommendations for reporting of synovial histopathology in mouse models of OA.

Methods

Coronal and sagittal sections from male mouse knee joints subjected to destabilization of medial meniscus (DMM) or partial meniscectomy (PMX) were collected as part of other studies. Stains included Hematoxylin and Eosin (H&E), Toluidine Blue (T-Blue), and Safranin O/Fast Green (Saf-O). Four blinded readers graded pathological features (hyperplasia, cellularity, and fibrosis) at specific anatomic locations. Inter-reader agreement of each feature score was determined.

Results

There was acceptable to very good agreement when using 3–4 individual readers. After DMM and PMX, expected medial predominant changes in hyperplasia and cellularity were observed, with fibrosis noted at 12 weeks post-PMX. Synovial changes were consistent from section to section in the mid-joint area. When comparing stains, H&E and T-blue resulted in better agreement compared to Saf-O stain.

Conclusions

To account for the pathologic and anatomic variability in synovial pathology and allow for a more standardized evaluation that can be compared across studies, we recommend evaluating a minimum set of 3 pathological features at standardized anatomic areas. Further, we suggest reporting individual feature scores separately before relying on a single summed “synovitis” score. H&E or T-blue are preferred, inter-reader agreement for each feature should be considered.

目的：滑膜病变与骨关节炎（OA）患者的疼痛有关。人类 OA 滑膜变化的显微镜分级系统已经得到描述，但还需要一种适用于小鼠 OA 模型的标准化方法。我们试图开发一种可重复的方法，并提出一套报告小鼠 OA 模型滑膜组织病理学的最低建议：作为其他研究的一部分，我们收集了雄性小鼠膝关节的冠状切片和矢状切片，这些关节均接受了内侧半月板失稳（DMM）或半月板部分切除术（PMX）。染色剂包括苏木精和伊红（H&E）、甲苯胺蓝（T-Blue）和沙弗林 O/快绿（Saf-O）。四名双盲阅读者对特定解剖位置的病理特征（增生、细胞性和纤维化）进行评分。结果：结果：使用 3-4 名读片员进行评分时，一致性从可以接受到非常好。在DMM和PMX术后，观察到增生和细胞性以内侧为主的预期变化，并在PMX术后12周出现纤维化。关节中段各切片的滑膜变化一致。与 Saf-O 染色法相比，H&E 和 T-blue 染色法的一致性更好：为了考虑滑膜病理学和解剖学的可变性，并使评估更加标准化，以便在不同的研究中进行比较，我们建议在标准化的解剖区域至少评估一组 3 个病理特征。此外，我们建议在依赖单一的 "滑膜炎 "总分之前，先分别报告各个特征的得分。首选 H&E 或 T-蓝染色，并应考虑每个特征的读片者之间的一致性。

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引用次数: 0

The coexistence of diabetes, hypertension and obesity is associated with worse pain outcomes following exercise for osteoarthritis: A cohort study on 80,893 patients 糖尿病、高血压和肥胖并存与骨关节炎运动后疼痛加重有关：一项针对 80,893 名患者的队列研究。

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2024-05-29 DOI: 10.1016/j.joca.2024.05.005

Objectives

To investigate how the co-occurrence of diabetes, hypertension and overweight/obesity is associated with pain following an exercise intervention for knee and hip osteoarthritis (OA).

Methods

Register-based cohort study. We included people from the Swedish Osteoarthritis Register who underwent education and exercise for knee or hip OA. Diabetes and hypertension were defined using medical records and dispensation of medication. Body Mass Index (BMI) was used to identify people with overweight (≥25 to <30), and obesity (≥30). We used linear mixed-effect models with patients nested into clinics to estimate the associations between the exposures and pain (Numeric Rating Scale 0–10), adjusting for age, sex, education, and physical activity.

Results

We analysed 80,893 patients with knee or hip OA. The accumulation of metabolic conditions was associated with worse pain at baseline and follow-ups. When obesity, hypertension and diabetes coexisted, patients treated for knee OA reported more pain at baseline (adjusted mean pain difference 0.9 [95 %CI: 0.8; 1.0]), 3 months (1.0 [0.9; 1.1]) and 12 months (1.3 [1.1; 1.4]) compared to those without any of the conditions. Similar results were observed for patients treated for hip OA when obesity, hypertension and diabetes coexisted (baseline (0.7 [0.5; 0.8], 3 (0.8[0.6; 1.0]) and 12 months (1.1[0.8; 1.3]).

Conclusions

When diabetes, hypertension and obesity coexist with OA, patients not only experience heightened baseline pain compared to metabolically healthy individuals, but the disparity increases after an education and exercise intervention suggesting that a one-size-fits-all approach may be inadequate in addressing the complex interplay between metabolic health and OA.

目的研究膝关节和髋关节骨性关节炎（OA）运动干预后，糖尿病、高血压和超重/肥胖的并发症与疼痛的关系：基于登记的队列研究。我们从瑞典骨关节炎登记册中纳入了接受过膝关节或髋关节OA教育和锻炼的患者。糖尿病和高血压是通过医疗记录和配药确定的。体重指数（BMI）用于确定超重者（≥25至50）：我们分析了 80,893 名膝关节或髋关节 OA 患者。新陈代谢状况的累积与基线和随访时疼痛的恶化有关。当肥胖、高血压和糖尿病并存时，与没有上述任何病症的患者相比，接受膝关节 OA 治疗的患者在基线（调整后的平均疼痛差异为 0.9 [95%CI: 0.8; 1.0]）、3 个月（1.0 [0.9; 1.1]）和 12 个月（1.3 [1.1; 1.4]）时报告的疼痛更严重。对于同时患有肥胖、高血压和糖尿病的髋关节OA患者（基线（0.7[0.5; 0.8]，3个月（0.8[0.6; 1.0]）和12个月（1.1[0.8; 1.3]），也观察到了类似的结果：结论：当糖尿病、高血压和肥胖与 OA 同时存在时，与代谢健康的人相比，患者不仅基线疼痛加剧，而且在接受教育和锻炼干预后，这种差异还会扩大，这表明 "一刀切 "的方法可能不足以解决代谢健康与 OA 之间复杂的相互作用。

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引用次数: 0

Repurposing drugs for the treatment of osteoarthritis 重新利用药物治疗骨关节炎。

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2024-05-29 DOI: 10.1016/j.joca.2024.05.008

Objective

Currently, no disease-modifying therapies for osteoarthritis (OA) exist, and attempts to identify novel cellular targets have been challenging. Risk factors for OA include advanced age, obesity, and metabolic syndrome. This creates an attractive opportunity to repurpose existing drugs that are used to treat comorbidities commonly encountered in patients with OA, if those drugs possess OA disease modifying properties.

Methods

This narrative review incorporates findings from knee or hand OA randomized clinical trials, post-hoc clinical trial analyses, prospective cohort studies, and observational data.

Results

Drugs used for the treatment of rheumatoid arthritis (methotrexate; TNFa, IL-1, and IL-6 pathway inhibitors; hydroxychloroquine), atopic/allergic disease (anti-histamines), osteoporosis (bisphosphonates and vitamin D), type 2 diabetes (metformin and GLP-1 agonists), and cardiovascular disease (atorvastatin, fish oil, and beta blockers) were reviewed for their potential benefit in OA. This review outlines the successful attributes of repurposed drugs, the challenges in repurposing drugs, and strategies for future clinical trials to support OA drug repurposing. Potential drug candidates for OA may be identified through the use of existing datasets and via collaborations with researchers in other fields to include OA endpoints in future clinical trials.

Conclusion

Given the association of OA with several commonly treated comorbidities, drug repurposing is an appealing approach that could provide a favorable benefit-to-risk ratio for chronic OA treatment.

目的：目前，还没有针对骨关节炎（OA）的疾病调节疗法，而试图确定新的细胞靶点一直是一项挑战。骨关节炎的风险因素包括高龄、肥胖和代谢综合征。这为重新利用用于治疗 OA 患者常见合并症的现有药物（如果这些药物具有改变 OA 疾病的特性）创造了一个极具吸引力的机会：本叙述性综述综合了膝关节或手部OA随机临床试验、临床试验后分析、前瞻性队列研究和观察性数据的结果：结果：综述了用于治疗类风湿性关节炎（甲氨蝶呤；TNFa、IL-1 和 IL-6 通路抑制剂；羟氯喹）、特应性/过敏性疾病（抗组胺药）、骨质疏松症（双磷酸盐类和维生素 D）、2 型糖尿病（二甲双胍和 GLP-1 激动剂）和心血管疾病（阿托伐他汀、鱼油和 β 受体阻滞剂）的药物对 OA 的潜在益处。本综述概述了再利用药物的成功特性、再利用药物所面临的挑战以及支持 OA 药物再利用的未来临床试验策略。通过使用现有数据集，并与其他领域的研究人员合作，将OA终点纳入未来的临床试验中，可确定OA的潜在候选药物：鉴于OA与几种常见的合并症有关，药物再利用是一种有吸引力的方法，可为慢性OA治疗提供有利的收益风险比。

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引用次数: 0

Chondrocyte autophagy mediated by T-2 toxin via AKT/TSC/Rheb/mTOR signaling pathway and protective effect of CSA-SeNP T-2毒素通过AKT/TSC/Rheb/mTOR信号通路介导的软骨细胞自噬和CSA-SeNP的保护作用。

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2024-05-28 DOI: 10.1016/j.joca.2024.05.007

Objective

Kashin-Beck disease (KBD) is an endemic, degenerative, and cartilage-damaging disease for which low selenium and T-2 toxins are considered environmental pathogenic factors. This study aimed to investigate the molecular mechanisms of autophagy in cartilage damage caused by T-2 toxin and the protective effect of chondroitin sulfate A nano-elemental selenium (CSA-SeNP) on the cartilage.

Methods

KBD chondrocytes and C28/I2 human chondrocyte cell lines were used. T-2 toxin, AKT inhibitor, and CSA-SeNP treatment experiments were conducted separately, with a treatment time of 24 h. Autophagy was monitored using MDC staining, and mRFP-GFP-LC3 adenovirus, respectively. RT-qPCR and western blotting were used to detect the expression of the relevant genes and proteins.

Results

The suppression of autophagy observed in KBD chondrocytes was replicated by applying 10 ng/mL T-2 toxin to C28/I2 chondrocytes for 24 h. The AKT/TSCR/Rheb/mTOR signaling pathway was activated by T-2 toxin, which inhibits autophagy. The supplementation with CSA-SeNP alleviated the inhibition of autophagy by T-2 toxin through the AKT/TSCR/Rheb/mTOR signaling pathway.

Conclusions

Loss of autophagy regulated by the AKT/TSCR/Rheb/mTOR signaling pathway plays an important role in cartilage damage caused by T-2 toxin. CSA-SeNP supplementation attenuated inhibition of autophagy in chondrocytes by T-2 toxin by modulating this signaling pathway. These findings provide promising new targets for the prevention and treatment of cartilage disease.

目的：卡申-贝克病（KBD）是一种地方性、退行性和软骨损伤性疾病，低硒和T-2毒素被认为是其环境致病因素。本研究旨在探讨 T-2 毒素导致软骨损伤的自噬分子机制，以及硫酸软骨素 A 纳米元素硒（CSA-SeNP）对软骨的保护作用：方法：采用 KBD 软骨细胞和 C28/I2 人类软骨细胞系。分别进行 T-2 毒素、AKT 抑制剂和 CSA-SeNP 处理实验，处理时间为 24 小时。分别使用 MDC 染色和 mRFP-GFP-LC3 腺病毒监测自噬。采用 RT-qPCR 和 Western 印迹法检测相关基因和蛋白质的表达：结果：在C28/I2软骨细胞中应用10 ng/mL的T-2毒素24小时后，在KBD软骨细胞中观察到的自噬抑制得到了复制。T-2 毒素激活了抑制自噬的 AKT/TSCR/Rheb/mTOR 信号通路。补充 CSA-SeNP 可通过 AKT/TSCR/Rheb/mTOR 信号通路缓解 T-2 毒素对自噬的抑制：结论：AKT/TSCR/Rheb/mTOR 信号通路调控的自噬损失在 T-2 毒素造成的软骨损伤中发挥了重要作用。补充 CSA-SeNP 可通过调节这一信号通路，减轻 T-2 毒素对软骨细胞自噬的抑制作用。这些发现为软骨疾病的预防和治疗提供了前景广阔的新靶点。

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引用次数: 0

Discovery of calcite as a new pro-inflammatory calcium-containing crystal in human osteoarthritic synovial fluid 发现方解石是人体骨关节炎滑液中一种新的促炎含钙晶体。

IF 7.2 2区医学 Q1 ORTHOPEDICS

Osteoarthritis and Cartilage

Pub Date : 2024-05-26 DOI: 10.1016/j.joca.2024.05.004

Objective

We aimed to characterize calcium-containing crystals present in synovial fluid from patients with knee osteoarthritis (OA) using Raman spectroscopy, and specifically investigate the biological effects of calcite crystals.

Design

Thirty-two synovial fluid samples were collected pre-operatively from knee OA patients undergoing total joint arthroplasty. An integrated Raman polarized light microscope was used for identification of crystals in synovial fluid. Human peripheral blood mononuclear cells (PBMC’s), human OA articular chondrocytes (HACs) and fibroblast-like synoviocytes (FLSs) were exposed to calcite crystals. Expression of relevant cytokines and inflammatory genes were measured using enzyme-linked immuno sorbent assay (ELISA) and real-time polymerase chain reaction (PCR).

Results

Various calcium-containing crystals were identified, including calcium pyrophosphate (37.5 %) and basic calcium phosphate (21.8 %), but they were never found simultaneously in the same OA synovial fluid sample. For the first time, we discovered the presence of calcite crystals in 93.8 % of the samples, while dolomite was detected in 25 % of the cases. Characterization of the cellular response to calcite crystal exposure revealed increased production of innate immune-derived cytokines by PBMC’s, when co-stimulated with lipopolysaccharide (LPS). Additionally, calcite crystal stimulation of HACs and FLSs resulted in enhanced secretion of pro-inflammatory molecules and alterations in the expression of extracellular matrix remodeling enzymes.

Conclusions

This study highlights the unique role of Raman spectroscopy in OA crystal research and identified calcite as a novel pro-inflammatory crystal type in OA synovial fluid. Understanding the role of specific crystal species in the OA joint may open new avenues for pharmacological interventions and personalized approaches to treating OA.

目的：我们旨在利用拉曼光谱分析膝关节骨性关节炎（OA）患者滑液中含钙晶体的特征，并特别研究方解石晶体的生物效应：设计：从接受全关节置换术的膝关节 OA 患者中收集 32 份术前滑液样本。使用集成拉曼偏振光显微镜鉴定滑液中的晶体。人外周血单核细胞（PBMC）、人 OA 关节软骨细胞（HAC）和成纤维细胞样滑膜细胞（FLS）暴露于方解石晶体。使用酶联免疫吸附和实时 PCR 检测了相关细胞因子和炎症基因的表达：结果：我们发现了多种含钙晶体，包括焦磷酸钙（37.5%）和碱式磷酸钙（21.8%），但它们从未同时出现在同一 OA 滑液样本中。我们首次在 93.8% 的样本中发现了方解石晶体，而在 25% 的病例中检测到了白云石。对暴露于方解石晶体后的细胞反应进行表征后发现，在与脂多糖（LPS）共同刺激下，外周血单核细胞（PBMC）产生的先天性免疫衍生细胞因子增多。此外，方解石晶体刺激 HACS 和 FLSs 会导致促炎分子的分泌增强，细胞外基质重塑酶的表达发生变化：本研究强调了拉曼光谱在 OA 晶体研究中的独特作用，并发现方解石是 OA 滑液中一种新型的促炎晶体类型。了解特定晶体类型在 OA 关节中的作用可能会为药物干预和个性化治疗 OA 开辟新的途径。

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