Early changes in cartilage pericellular matrix micromechanobiology portend the onset of post-traumatic osteoarthritis
Early changes in cartilage pericellular matrix micromechanobiology portend the onset of post-traumatic osteoarthritis
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DOI：
10.1016/j.actbio.2020.05.005
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发表时间：
2020-07-15
影响因子：
9.7
通讯作者：
Han, Lin
中科院分区：
文献类型：
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作者：
Chery, Daphney R.;Han, Biao;Han, Lin
软骨的细胞周基质（pericellular matrix，PCM）是围绕每个软骨细胞的结构独特的微域，并且对健康组织中的细胞稳态和细胞-基质相互作用至关重要。这项研究质疑PCM是疾病的起始点还是更广泛基质变性的牺牲品。为了解决这个问题，我们询问了PCM的机械性能和软骨细胞随着创伤后骨关节炎（PTOA）的发展的机械反应性。为此，我们将Kawamoto的膜辅助冷冻切片与免疫荧光引导的AFM纳米力学映射相结合，并量化了小鼠软骨PCM和进一步去除的细胞外基质的微尺度模量。使用内侧半月板（DMM）PTOA小鼠模型的不稳定性，我们表明，PCM微观力学的下降是明显的，早在受伤后3天，这之前的变化，在散装ECM属性和明显的迹象软骨损伤。我们还表明，作为改变PCM属性的结果，软骨细胞在响应机械挑战（低渗应力）的钙动员显着中断。这些异常的变化，软骨细胞的微观机械生物学作为DMM的结果，可以部分阻断PCM重塑的早期抑制。总的来说，这些结果表明，PCM微观机械生物学的变化是PTOA开始的主要指标，并且疾病起源于软骨PCM。这一见解将指导早期检测方法的发展，以及基于小分子的治疗方法，可以阻止早期异常重塑这一关键的软骨microdomain，以减缓或逆转疾病的进展。重要性声明创伤后骨关节炎（PTOA）是一种常见的肌肉骨骼疾病，折磨年轻人，并没有有效的早期检测或干预的策略。本研究确定，软骨细胞周基质（PCM）微模量的降低是PTOA启动的最早事件之一，这反过来又损害了软骨细胞的机械敏感性活动，导致软骨退化的恶性循环。拯救PCM的完整性具有恢复正常软骨细胞机械敏感性稳态和防止软骨进一步退化的潜力。我们的研究结果使得能够开发针对PCM变化的早期OA检测方法，以及可以阻止这一关键微域中的早期异常重塑以减缓或逆转疾病进展的治疗策略。(C)2020 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
The pericellular matrix (PCM) of cartilage is a structurally distinctive microdomain surrounding each chondrocyte, and is pivotal to cell homeostasis and cell-matrix interactions in healthy tissue. This study queried if the PCM is the initiation point for disease or a casualty of more widespread matrix degeneration. To address this question, we queried the mechanical properties of the PCM and chondrocyte mechanoresponsivity with the development of post-traumatic osteoarthritis (PTOA). To do so, we integrated Kawamoto's film-assisted cryo-sectioning with immunofluorescence-guided AFM nanomechanical mapping, and quantified the microscale modulus of murine cartilage PCM and further-removed extracellular matrix. Using the destabilization of the medial meniscus (DMM) murine model of PTOA, we show that decreases in PCM micromechanics are apparent as early as 3 days after injury, and that this precedes changes in the bulk ECM properties and overt indications of cartilage damage. We also show that, as a consequence of altered PCM properties, calcium mobilization by chondrocytes in response to mechanical challenge (hypo-osmotic stress) is significantly disrupted. These aberrant changes in chondrocyte micromechanobiology as a consequence of DMM could be partially blocked by early inhibition of PCM remodeling. Collectively, these results suggest that changes in PCM micromechanobiology are leading indicators of the initiation of PTOA, and that disease originates in the cartilage PCM. This insight will direct the development of early detection methods, as well as small molecule-based therapies that can stop early aberrant remodeling in this critical cartilage microdomain to slow or reverse disease progression.Statement of SignificancePost-traumatic osteoarthritis (PTOA) is one prevalent musculoskeletal disease that afflicts young adults, and there are no effective strategies for early detection or intervention. This study identifies that the reduction of cartilage pericellular matrix (PCM) micromodulus is one of the earliest events in the initiation of PTOA, which, in turn, impairs the mechanosensitive activities of chondrocytes, contributing to the vicious loop of cartilage degeneration. Rescuing the integrity of PCM has the potential to restore normal chondrocyte mechanosensitive homeostasis and to prevent further degradation of cartilage. Our findings enable the development of early OA detection methods targeting changes in the PCM, and treatment strategies that can stop early aberrant remodeling in this critical microdomain to slow or reverse disease progression. (C) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.