Regulating Kynurenine-Mediated Suppression of CLOCK by miR-30b-5p in Knee Osteoarthritis

The circadian rhythms change with senescence and its disruption increases the risk of knee osteoarthritis (KOA), considered as a pathological change of aging in bodies. However, the occurrence mechanism of disordered circadian rhythms in KOA is still unclear. Herein, it is observed that the content of circadian locomotor output cycles kaput (CLOCK), a driven protein for circadian rhythms, significantly decreased in articular cartilage tissue from KOA patients compared with that from non-KOA patients. On the contrary, the levels of miR-30b-5p and kynurenine (KYN), two substances changed with age, in articular cartilage tissue from KOA patients was higher than that from non-KOA patients. Next, a positive controlling of KYN on miR-30b-5p was also detected in chondrocytes isolated from non-KOA cartilage, and a negatively targeting action of miR-30b-5p on CLOCK was confirmed by dual-luciferase reporter assay. Most importantly, not only KYN induced a significant decrease of CLOCK mRNA/protein, but also suppressing miR-30b-5p may weaken obviously KYN-mediated downregulation of CLOCK protein in non-KOA chondrocytes. Lastly, it was also presented that the circadian rhythm of CLOCK was disordered by KYN, and the KYN-induced disordered circadian rhythm of CLOCK is partly reversed by reducing miR-30b-5p. These data suggest that KYN may be considered as a regulatory factor for disordered circadian rhythms of KOA through miR-30b-5p targeting CLOCK.