Abstract：
The availability of human cell-based models capturing molecular processes of cartilage degeneration can facilitate development of disease-modifying therapies for osteoarthritis [1], a currently unmet clinical need. Here, by imposing specific inflammatory challenges upon mesenchymal stromal cells at a defined stage of chondrogenesis, we engineered a human organotypic model which recapitulates main OA pathological traits such as chondrocyte hypertrophy, cartilage matrix mineralization, enhanced catabolism and mechanical stiffening. To exemplify the utility of the model, we exposed the engineered OA cartilage organoids to factors known to attenuate pathological features, including IL-1Ra, and carried out mass spectrometry-based proteomics. We identified that IL-1Ra strongly reduced production of the transcription factor CCAAT/enhancer-binding protein beta [2] and demonstrated that inhibition of the C/EBPβ-activating kinases could revert the degradative processes. Human OA cartilage organoids thus represent a relevant tool towards the discovery of new molecular drivers of cartilage degeneration and the assessment of therapeutics targeting associated pathways.
摘要：
捕获软骨退化的分子过程的基于人类细胞的模型的可用性可以促进骨关节炎的疾病修饰疗法的发展[1]，目前尚未满足的临床需求。这里,通过在软骨形成的确定阶段对间充质基质细胞施加特定的炎症挑战，我们设计了一个人类器官型模型，该模型概括了主要的OA病理特征，如软骨细胞肥大，软骨基质矿化，增强的分解代谢和机械硬化。为了举例说明该模型的实用性，我们将工程OA软骨类器官暴露于已知可减弱病理特征的因子，包括IL-1Ra，并进行了基于质谱的蛋白质组学。我们发现IL-1Ra大大降低了转录因子CCAAT/增强子结合蛋白β的产生[2]，并证明了C/EBPβ激活激酶的抑制可以逆转降解过程。因此,人OA软骨类器官代表了发现软骨退化的新分子驱动剂和评估靶向相关途径的治疗剂的相关工具。
