Objective

This study was performed to characterize selected rhodanine derivatives as potential preclinical disease-modifying drugs for experimental osteoarthritis (OA) in mice.

Methods

Three rhodanine derivatives, designated rhodanine (R)-501, R-502, and R-503, were selected as candidate OA disease-modifying drugs. Their effects were evaluated by intra-articular (IA) injection in OA mouse models induced by DMM (destabilization of the medial meniscus) or adenoviral overexpression in joint tissues of hypoxia-inducible factor (HIF)-2α or zinc importer ZIP8. The regulatory mechanisms impacted by the rhodanine derivatives were examined in primary-culture chondrocytes and fibroblast-like synoviocytes (FLS).

Results

All three rhodanine derivatives inhibited OA development caused by DMM or overexpression of HIF-2α or ZIP8. Compared to vehicle-treated group, for example, IA injection of R-501 in DMM-operated mice reduced median OARSI grade from 3.78 (IQR 3.00–5.00) to 1.89 (IQR 0.94–2.00, P = 0.0001). R-502 and R-503 also reduced from 3.67 (IQR 2.11–4.56) to 2.00 (IQR 1.00–2.00, P = 0.0030) and 2.00 (IQR 1.83–2.67, P = 0.0378), respectively. Mechanistically, the rhodanine derivatives inhibited the nuclear localization and transcriptional activity of HIF-2α in chondrocytes and FLS. They did not bind to Zn²⁺ or modulate Zn²⁺ homeostasis in chondrocytes or FLS; instead, they inhibited the nuclear localization and transcriptional activity of the Zn²⁺-dependent transcription factor, MTF1. HIF-2α, ZIP8, and interleukin-1β could upregulate matrix-degrading enzymes in chondrocytes and FLS, and the rhodanine derivatives inhibited these effects.

Conclusion

IA administration of rhodanine derivatives significantly reduced OA pathogenesis in various mouse models, demonstrating that these derivatives have disease-modifying therapeutic potential against OA pathogenesis.

中文翻译：

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罗丹宁衍生物作为实验性小鼠骨关节炎潜在疾病改善药物的表征

客观的

本研究旨在将选定的罗丹宁衍生物表征为小鼠实验性骨关节炎 (OA) 的潜在临床前疾病改善药物。

方法

三种罗丹宁衍生物，命名为罗丹宁 (R)-501、R-502 和 R-503，被选为候选 OA 疾病缓解药物。通过在由 DMM（内侧半月板不稳定）诱导的 OA 小鼠模型中关节内 (IA) 注射或在缺氧诱导因子 (HIF)-2α 或锌导入物 ZIP8 的关节组织中过表达腺病毒来评估它们的效果。在原代培养软骨细胞和成纤维细胞样滑膜细胞 (FLS) 中检查了受罗丹宁衍生物影响的调节机制。

结果

所有三种罗丹宁衍生物均抑制由 DMM 或 HIF-2α 或 ZIP8 过表达引起的 OA 发展。例如，与载体治疗组相比，在 DMM 手术小鼠中 IA 注射 R-501 将中位 OARSI 等级从 3.78 (IQR 3.00–5.00) 降低到 1.89 (IQR 0.94–2.00, P  = 0.0001)。R-502 和 R-503 也分别从 3.67 (IQR 2.11–4.56) 降低到 2.00 (IQR 1.00–2.00, P  = 0.0030) 和 2.00 (IQR 1.83–2.67, P  = 0.0378)。从机制上讲，罗丹宁衍生物抑制 HIF-2α 在软骨细胞和 FLS 中的核定位和转录活性。它们不与 Zn ²⁺结合或调节 Zn ²⁺软骨细胞或 FLS 的体内平衡；^{相反，它们抑制了 Zn 2+}依赖性转录因子 MTF1的核定位和转录活性。HIF-2α、ZIP8 和白细胞介素 1β 可以上调软骨细胞和 FLS 中的基质降解酶，而罗丹宁衍生物可抑制这些作用。

结论

IA 给药罗丹宁衍生物显着降低了各种小鼠模型中的 OA 发病机制，证明这些衍生物对 OA 发病机制具有改善疾病的治疗潜力。