Chery Daphney R, Han Biao, Li Qing, Zhou Ying, Heo Su-Jin, Kwok Bryan, Chandrasekaran Prashant, Wang Chao, Qin Ling, Lu X Lucas, Kong Dehan, Enomoto-Iwamoto Motomi, Mauck Robert L, Han Lin
School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, United States.
Department of Statistical Sciences, University of Toronto, Toronto, ON M5S 3G3, Canada.
Acta Biomater. 2020 Jul 15;111:267-278. doi: 10.1016/j.actbio.2020.05.005. Epub 2020 May 16.
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 SIGNIFICANCE: Post-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.
软骨的细胞周基质（PCM）是围绕每个软骨细胞的结构独特的微区，对健康组织中的细胞稳态和细胞 - 基质相互作用至关重要。本研究探讨PCM是疾病的起始点还是更广泛基质退变的受害者。为解决这个问题，我们研究了创伤后骨关节炎（PTOA）发展过程中PCM的力学性能和软骨细胞的机械反应性。为此，我们将川本的薄膜辅助冷冻切片与免疫荧光引导的原子力显微镜纳米力学测绘相结合，量化了小鼠软骨PCM和更远距离的细胞外基质的微观尺度模量。使用PTOA的内侧半月板不稳定（DMM）小鼠模型，我们发现PCM微观力学的降低早在损伤后3天就很明显，并且这先于整体细胞外基质特性的变化和软骨损伤的明显迹象。我们还表明，由于PCM特性的改变，软骨细胞对机械挑战（低渗应激）的钙动员受到显著破坏。DMM导致的软骨细胞微观力学生物学的这些异常变化可通过早期抑制PCM重塑而部分阻断。总体而言，这些结果表明PCM微观力学生物学的变化是PTOA起始的主要指标，并且疾病起源于软骨PCM。这一见解将指导早期检测方法以及基于小分子的疗法的开发，这些疗法可以阻止这个关键软骨微区的早期异常重塑，以减缓或逆转疾病进展。
创伤后骨关节炎（PTOA）是一种困扰年轻人的常见肌肉骨骼疾病，目前尚无有效的早期检测或干预策略。本研究确定软骨细胞周基质（PCM）微观模量的降低是PTOA起始的最早事件之一，进而损害软骨细胞的机械敏感活性，导致软骨退变的恶性循环。恢复PCM的完整性有可能恢复正常的软骨细胞机械敏感稳态，并防止软骨进一步退化。我们的研究结果有助于开发针对PCM变化的早期骨关节炎检测方法，以及能够阻止这个关键微区早期异常重塑以减缓或逆转疾病进展的治疗策略。
