JCI Insight. 2022 Oct 4;7(20):e160702. doi: 10.1172/jci.insight.160702.
No disease-modifying drug exists for osteoarthritis (OA). Despite success in animal models, candidate drugs continue to fail in clinical trials owing to the unmapped interpatient heterogeneity and disease complexity. We used a single-cell platform based on cytometry by time-of-flight (cyTOF) to precisely outline the effects of candidate drugs on human OA chondrocytes. OA chondrocytes harvested from patients undergoing total knee arthroplasty were treated with 2 drugs, an NF-κB pathway inhibitor, BMS-345541, and a chondroinductive small molecule, kartogenin, that showed preclinical success in animal models for OA. cyTOF conducted with 30 metal isotope-labeled antibodies parsed the effects of the drugs on inflammatory, senescent, and chondroprogenitor cell populations. The NF-κB pathway inhibition decreased the expression of p-NF-κB, HIF2A, and inducible NOS in multiple chondrocyte clusters and significantly depleted 4 p16ink4a-expressing senescent populations, including NOTCH1+STRO1+ chondroprogenitor cells. While kartogenin also affected select p16ink4a-expressing senescent clusters, there was a less discernible effect on chondroprogenitor cell populations. Overall, BMS-345541 elicited a uniform drug response in all patients, while only a few responded to kartogenin. These studies demonstrate that a single-cell cyTOF-based drug screening platform can provide insights into patient response assessment and patient stratification.
目前尚无治疗骨关节炎 (OA) 的药物。尽管在动物模型中取得了成功，但由于患者间异质性和疾病复杂性尚未明确，候选药物在临床试验中仍不断失败。我们使用基于飞行时间（cyTOF）的单细胞平台精确描绘候选药物对人类 OA 软骨细胞的作用。从接受全膝关节置换术的患者中采集 OA 软骨细胞，用两种药物进行处理，一种是 NF-κB 通路抑制剂 BMS-345541，另一种是软骨诱导小分子 kartogenin，该药在 OA 的动物模型中具有临床前成功。用 30 种金属同位素标记的抗体进行的 cyTOF 分析解析了药物对炎症、衰老和软骨祖细胞群体的影响。NF-κB 通路抑制降低了多个软骨细胞簇中 p-NF-κB、HIF2A 和诱导型 NOS 的表达，并显著耗尽了包括 NOTCH1+STRO1+软骨祖细胞在内的 4 个 p16ink4a 表达的衰老群体。虽然 kartogenin 也影响了部分 p16ink4a 表达的衰老群体，但对软骨祖细胞群体的影响则不太明显。总体而言，BMS-345541 在所有患者中引起了一致的药物反应，而只有少数患者对 kartogenin 有反应。这些研究表明，基于单细胞 cyTOF 的药物筛选平台可以提供有关患者反应评估和患者分层的见解。
