Osteoarthritis (OA) is characterized by irreversible cartilage degradation with very limited therapeutic interventions. Drug candidates targeted at prototypic players had limited success until now and systems based approaches might be necessary. Consequently, drug evaluation platforms should consider the biological complexity looking beyond well-known contributors of OA. In this study an ex vivo model of cartilage degradation, combined with measuring releases of 27 proteins, was utilized to study 9 drug candidates. After an initial single drug evaluation step the 3 most promising compounds were selected and employed in an exhaustive combinatorial experiment. The resulting most and least promising treatment candidates were selected and validated in an independent study. This included estimation of mechanical properties via finite element modelling (FEM) and quantification of cartilage degradation as glycosaminoglycan (GAG) release. The most promising candidate showed increase of Young’s modulus, decrease of hydraulic permeability and decrease of GAG release. The least promising candidate exhibited the opposite behaviour. The study shows the potential of a novel drug evaluation platform in identifying treatments that might reduce cartilage degradation. It also demonstrates the promise of exhaustive combination experiments and a connection between chondrocyte responses at the molecular level with changes of biomechanical properties at the tissue level.

骨关节炎 (OA) 的特点是不可逆的软骨退化，治疗干预非常有限。迄今为止，针对原型参与者的候选药物取得的成功有限，可能需要基于系统的方法。因此，药物评估平台应该考虑超越 OA 知名贡献者的生物学复杂性。在这项研究中，软骨退化的离体模型，结合测量 27 种蛋白质的释放，被用来研究 9 种候选药物。在最初的单一药物评估步骤之后，选择了 3 种最有希望的化合物并将其用于详尽的组合实验。由此产生的最有希望和最没有希望的治疗候选者在一项独立研究中被选择和验证。这包括通过有限元建模 (FEM) 估计机械性能以及随着糖胺聚糖 (GAG) 释放对软骨降解进行量化。最有希望的候选物显示出杨氏模量增加、水力渗透率降低和 GAG 释放减少。最没有希望的候选人表现出相反的行为。该研究显示了一种新型药物评估平台在确定可能减少软骨退化的治疗方法方面的潜力。它还证明了详尽组合实验的前景以及分子水平的软骨细胞反应与组织水平的生物力学特性变化之间的联系。渗透率降低和 GAG 释放减少。最没有希望的候选人表现出相反的行为。该研究显示了一种新型药物评估平台在确定可能减少软骨退化的治疗方法方面的潜力。它还证明了详尽组合实验的前景以及分子水平的软骨细胞反应与组织水平的生物力学特性变化之间的联系。渗透率降低和 GAG 释放减少。最没有希望的候选人表现出相反的行为。该研究显示了一种新型药物评估平台在确定可能减少软骨退化的治疗方法方面的潜力。它还证明了详尽组合实验的前景以及分子水平的软骨细胞反应与组织水平的生物力学特性变化之间的联系。