Zhu Linyi, Lin Weifeng, Kluzek Monika, Miotla-Zarebska Jadwiga, Batchelor Vicky, Gardiner Matthew, Chan Chris, Culmer Peter, Chanalaris Anastasios, Goldberg Ronit, Klein Jacob, Vincent Tonia L
Kennedy Institute of Rheumatology, Centre for OA Pathogenesis Versus Arthritis, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK.
Dept. of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot 7610001, Israel; Key Laboratory of Bio-Inspired Smart Interfacial Science and Technology of Ministry of Education, School of Chemistry, Beihang University, Beijing 100191.
Acta Biomater. 2025 May 15;198:366-376. doi: 10.1016/j.actbio.2025.04.022. Epub 2025 Apr 10.
Osteoarthritis (OA) is a widespread, debilitating joint disease associated with articular cartilage degradation. It is driven via mechano-inflammatory pathways, whereby catabolic genes in the cartilage-embedded chondrocytes are presumed up-regulated due to increased shear stress arising from friction at the cartilage surface as joints articulate. The enhanced expression of these cartilage-degrading and inflammatory genes leads to tissue degeneration. However, the nature of the stress, and how the cells within the joint respond to it, are poorly understood. Here we show, in a proof of concept study on a mouse model where surgical joint destabilisation has been carried out to induce OA, that the early up-regulation of the matrix metalloproteinase 3 (Mmp3) gene, a member of the matrix-degrading MMP family, and of the interleukin-1 beta (Il1b) gene, a key mediator of inflammatory response, are significantly suppressed when lipid-based lubricants are injected into the joints. We attribute this to the reduction in frictional stress on the chondrocytes due to the lubricant at the cartilage surface. At the same time, Timp1, a compression but not shear-stress sensitive gene, is unaffected by lubricant. Our results demonstrate that cartilage lubrication modulates catabolic gene regulation in OA, shed strong light on the nature of the chondrocytes' response to shear stress, and have clear implications for novel OA treatments. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) is a widespread, debilitating joint disease associated with degradation of the articular cartilage, the tissue that covers and protects the joint surfaces as they rotate. Such degradation is due to catabolic enzymes expressed by cartilage-embedded chondrocytes (the only cell type in cartilage) in response to mechanical stress. In this proof-of-concept study in a mouse OA model, we show that reduction of cartilage friction by liposome-based lubricants suppresses the production of the catabolic, OA-related genes in chondrocytes. Our findings provide direct evidence in an animal model that catabolic genes are induced in chondrocytes in a mechanosensitive manner, related to the friction at the cartilage surface, and identify putative novel OA treatments through efficient cartilage lubrication.
骨关节炎（OA）是一种常见的、使人衰弱的关节疾病，与关节软骨退化有关。它是通过机械炎症途径引发的，据此推测，由于关节活动时软骨表面摩擦产生的剪切应力增加，嵌入软骨的软骨细胞中的分解代谢基因会上调。这些软骨降解和炎症基因的表达增强会导致组织退化。然而，应力的性质以及关节内的细胞如何对其作出反应，目前仍知之甚少。在此，我们在一项概念验证研究中表明，在通过手术使关节不稳定以诱导OA的小鼠模型中，当向关节内注射脂质基润滑剂时，基质金属蛋白酶3（Mmp3）基因（基质降解MMP家族的成员）和白细胞介素-1β（Il1b）基因（炎症反应的关键介质）的早期上调受到显著抑制。我们将此归因于软骨表面的润滑剂降低了软骨细胞上的摩擦应力。同时，Timp1是一个对压缩敏感但对剪切应力不敏感的基因，不受润滑剂影响。我们的结果表明，软骨润滑可调节OA中的分解代谢基因调控，为软骨细胞对剪切应力的反应性质提供了重要线索，并且对新型OA治疗具有明确的意义。意义声明：骨关节炎（OA）是一种常见的、使人衰弱的关节疾病，与关节软骨退化有关，关节软骨是覆盖和保护关节面在其转动时的组织。这种退化是由于嵌入软骨的软骨细胞（软骨中唯一的细胞类型）响应机械应力而表达的分解代谢酶所致。在这项针对小鼠OA模型的概念验证研究中，我们表明基于脂质体的润滑剂减少软骨摩擦可抑制软骨细胞中与OA相关的分解代谢基因的产生。我们的研究结果在动物模型中提供了直接证据，证明分解代谢基因是以机械敏感的方式在软骨细胞中被诱导的，这与软骨表面的摩擦有关，并通过有效的软骨润滑确定了推定的新型OA治疗方法。
