Drugging the circadian clock feedback cycle to ameliorate cartilage degeneration
Drugging the circadian clock feedback cycle to ameliorate cartilage degeneration
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对生物钟反馈周期进行药物治疗以改善软骨退化
DOI：
10.1111/febs.16601
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发表时间：
2022-09-01
期刊：
影响因子：
5.4
通讯作者：
Zheng, Chao
中科院分区：
文献类型：
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作者：
He, Ting;Pang, Siyi;Zheng, Chao
外周生物钟减弱与骨关节炎 (OA) 有关，但尚不清楚给生物钟服用药物是否可以改善 OA。鉴于 ROR 和 REV-ERB 分别介导主时钟基因 BMAL1 的正转录反馈和负转录反馈，我们研究了 ROR 激动剂 Nobiletin (NOB) 和 SR1078 以及 REV-ERB 拮抗剂 SR8278 是否可以增强 BMAL1 表达并减轻软骨退化。 NOB 和 SR8278 促进 BMAL1 表达，并引起对 IL-1 β 诱导的软骨外植体变性的缓解作用，细胞密度和胶原合成增加以及分解代谢和胶原变性减轻就证明了这一点。尽管促进 BMAL1 表达，SR1078 同时抑制软骨细胞的合成代谢和分解代谢。与这些发现一致的是，NOB 和 SR8278（而非 SR1078）治疗可有效减轻手术诱导的 OA 小鼠模型中关节软骨的结构破坏。值得注意的是，NOB 和 SR8278 在 IL-1 β 诱导的人软骨外植体和永生化人软骨细胞变性中明显观察到了有益作用。此外，BMAL1 敲低测定表明，NOB 和 SR8278 增强了时钟功能，并一致地在 BMAL1 依赖性机制中提供针对合成代谢和分解代谢改变的保护。总的来说，我们的研究表明，针对 ROR 和 REV-ERB 来促进减弱的外周时钟可能是在 OA 背景下应用时间疗法的一条途径。
Dampened peripheral clocks have been linked to osteoarthritis (OA), yet it is unclear whether drugging the clock can ameliorate OA. Given that RORs and REV-ERBs mediate respectively, positive and negative transcriptional feedback of the master clock gene BMAL1, we investigate whether RORs agonist Nobiletin (NOB) and SR1078, and REV-ERBs antagonist SR8278 can enhance BMAL1 expression and attenuate cartilage degeneration. NOB and SR8278 promoted BMAL1 expression and elicited mitigating effects against IL-1 beta-induced degeneration of cartilage explants, as evidenced by increased cellular density and collagen synthesis along with alleviated catabolism and collagen denaturation. Despite promoted BMAL1 expression, SR1078 concomitantly suppressed chondrocyte anabolism and catabolism. Consistent with these findings, NOB and SR8278 treatment, but not SR1078, effectively attenuated structural destruction of articular cartilage in surgery-induced OA mouse models. Notably, the beneficial effects of NOB and SR8278 were evidently observed in IL-1 beta-induced degeneration of human cartilage explants and immortalized human chondrocytes. Moreover, BMAL1 knockdown assays indicated that NOB and SR8278 enhanced clock function and concordantly rendered protection against altered anabolism and catabolism in a BMAL1-dependent regime. Collectively, our study suggests that targeting RORs and REV-ERBs to promote the dampened peripheral clocks could be a route taken to apply chronotherapy within the context of OA.