Marrero-Berrios Ileana, Salter S Elina, Hirday Rishabh, Rabolli Charles P, Tan Andrea, Hung Clark T, Schloss Rene S, Yarmush Martin L
Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA.
Department of Biomedical Engineering, Columbia University, New York, NY, USA.
Osteoarthr Cartil Open. 2024 Jan 5;6(1):100432. doi: 10.1016/j.ocarto.2023.100432. eCollection 2024 Mar.
Osteoarthritis (OA) is a chronic joint disease, with limited treatment options, characterized by inflammation and matrix degradation, and resulting in severe pain or disability. Progressive inflammatory interaction among key cell types, including chondrocytes and macrophages, leads to a cascade of intra- and inter-cellular events which culminate in OA induction. In order to investigate these interactions, we developed a multi-cellular OA model, to characterize OA progression, and identify and evaluate potential OA therapeutics in response to mediators representing graded levels of inflammatory severity.
We compared macrophages, chondrocytes and their co-culture responses to "low" Interleukin-1 (IL-1) or "high" IL-1/tumor necrosis factor (IL-1/TNF) levels of inflammation. We also investigated response changes following the administration of dexamethasone (DEX) or mesenchymal stromal cell (MSC) treatment via a combination of gene expression and secretory changes, reflecting not only inflammation, but also chondrocyte function.
Inflamed chondrocytes presented an osteoarthritic-like phenotype characterized by high gene expression of pro-inflammatory cytokines and chemokines, up-regulation of ECM degrading proteases, and down-regulation of chondrogenic genes. Our results indicate that while MSC treatment attenuates macrophage inflammation directly, it does not reduce chondrocyte inflammatory responses, unless macrophages are present as well. DEX however, can directly attenuate chondrocyte inflammation.
Our results highlight the importance of considering multi-cellular interactions when studying complex systems such as the articular joint. In addition, our approach, using a panel of both inflammatory and chondrocyte functional genes, provides a more comprehensive approach to investigate disease biomarkers, and responses to treatment.
骨关节炎（OA）是一种慢性关节疾病，治疗选择有限，其特征为炎症和基质降解，可导致严重疼痛或残疾。包括软骨细胞和巨噬细胞在内的关键细胞类型之间进行性的炎症相互作用会引发一系列细胞内和细胞间事件，最终导致OA的发生。为了研究这些相互作用，我们构建了一个多细胞OA模型，以表征OA的进展，并识别和评估针对代表不同炎症严重程度水平的介质的潜在OA治疗方法。
我们比较了巨噬细胞、软骨细胞及其共培养物对“低”白细胞介素-1（IL-1）或“高”IL-1/肿瘤坏死因子（IL-1/TNF）炎症水平的反应。我们还通过基因表达和分泌分析相结合的方法，研究了地塞米松（DEX）或间充质基质细胞（MSC）治疗后反应的变化，这不仅反映炎症情况，还反映软骨细胞功能。
炎症软骨细胞呈现出骨关节炎样表型，其特征为促炎细胞因子和趋化因子的高基因表达、细胞外基质降解蛋白酶的上调以及软骨生成基因的下调。我们的结果表明，虽然MSC治疗可直接减轻巨噬细胞炎症，但除非同时存在巨噬细胞，否则它不会降低软骨细胞的炎症反应。然而，DEX可直接减轻软骨细胞炎症。
我们的结果突出了在研究诸如关节等复杂系统时考虑多细胞相互作用的重要性。此外，我们使用一组炎症和软骨细胞功能基因的方法，为研究疾病生物标志物和治疗反应提供了更全面的方法。
