Cartilage-specific knockout of miRNA-128a expression normalizes the expression of circadian clock genes (CCGs) and mitigates the severity of osteoarthritis

Abstract

Background: Micro-ribonucleic acids (miRNAs) are involved in osteoarthritis (OA) pathogenesis and clock-controlled genes (CCGs) regulation. However, the interaction between miRNAs and CCGs remains unclear. Methods: Human OA samples were used to assess CCGs expression. Cartilage-specific miR-128a knockout mouse model was established to investigate miR-128a′s role in OA pathogenesis. Destabilization of the medial meniscus (DMM) model was employed to simulate OA. Results: Transcription levels of nuclear receptor subfamily 1 group D member 2 (NR1D2) were lower in both human OA samples and wild-type mice undergoing DMM compared to non-OA counterparts. MiR-128a knockout mice showed reduced disturbances in micro-computed tomographic and kinematic parameters following DMM, as well as less severe histologic cartilage loss. Immunohistochemistry staining revealed a lesser decrease in NR1D2-positive chondrocytes after DMM in miR-128a knockout mice than in wild-type mice. NR1D2 agonist rescued the suppressed expression of cartilage anabolic factors and extracellular matrix deposition caused by miR-128a precursor. Conclusions: Cartilage-specific miR-128a knockout mice exhibited reduced severity, less disrupted kinematic parameters, and suppressed NR1D2 expression after DMM. NR1D2 enhanced the expression of cartilage anabolic factors and extracellular matrix deposition. These findings highlight the potential of employing miR-128a and CCG-targeted therapy for knee OA.

Keywords

• Osteoarthritis
• miRNA-128a
• NR1D2 (nuclear receptor subfamily 1 group D member 2)