Drugging the circadian clock feedback cycle to ameliorate cartilage degeneration. (1st September 2022)

• Record Type: Journal Article
• Authors: He, Ting; Pang, Siyi; Wang, Huanbo; Yun, Haitao; Hao, Xue; Jia, Liyuan; Liu, He; Wang, Di; Wang, Dong; Xu, Huiyun; Jie, Qiang; Yang, Liu; Zheng, Chao
• Is Part Of: FEBS journal. Volume 289:Number 21(2022)
• Page Start: 6643
• Page End: 6658
• Publication Date: 2022-09-01
• Subjects: Cartilage degeneration -- Circadian clock -- Nobiletin -- SR1078 -- SR8278; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.16601
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : 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‐1β‐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‐1β‐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. Abstract : There is growing evidence that the circadian clock plays a key role in osteoarthritis pathology. Rhythmic gene expression is generated and sustained by the BMAL1‐CLOCK heterodimer, whose activity is in turn modulated by a plethora of transcription factors, including nuclear receptor RORs and REV‐ERBs. In this study, He et al. provide evidence that RORs agonist Nobiletin and REV‐ERBs antagonist SR8278 promote BMAL1 expression and attenuate cartilage degeneration in vitro and in vivo, suggesting that manipulation of the circadian clock could provide a promising treatment strategy for osteoarthritis.