Inflammation Inhibits HECTD1 ‐Mediated AURKA Ubiquitination to Cause Extracellular Matrix Degradation in Osteoarthritis via Enhancing Cap‐Dependent mRNA Translation of ADAMTS12

ABSTRACT Osteoarthritis (OA) is a common joint disease, and chondrocyte extracellular matrix (ECM) degradation was closely associated with its progression. This study investigated the regulatory mechanisms of ECM degradation during OA development. A rat model of OA was established by anterior cruciate ligament transection (ACL‐T) and interleukin‐1 beta (IL‐1β)‐stimulated rat chondrocytes were used to simulate OA in vitro. Cartilage damage was evaluated by hematoxylin–eosin (HE) and safranin O‐fast green staining. The ECM content in chondrocytes was assessed by alcian blue staining. Real‐time quantitative PCR (RT‐qPCR), Western Blotting, immunohistochemical staining, and immunofluorescent staining were adopted to analyze associated molecule expression. Molecular mechanisms were elucidated by Co‐immunoprecipitation (Co‐IP) and GST pull‐down assay. We found that Aurora kinase A (AURKA), p‐eukaryotic translation initiation factor 4E (eIF4E), and ADAM metallopeptidase with thrombospondin type 1 motif 12 (ADAMTS12) levels were elevated in the human and rat cartilage tissues of OA, as well as IL‐1β‐exposed chondrocytes. AURKA inhibition restrained ECM degradation to relieve OA via down‐regulation of ADAMTS12. AURKA overexpression phosphorylated eIF4E, which promoted cap‐dependent translation of ADAMTS12. Moreover, DNA methyltransferase 1 (DNMT1)‐mediated methylation down‐regulated HECT domain E3 ubiquitin protein ligase 1 (HECTD1) in the OA model and consequently enhanced AURKA expression via inhibiting its ubiquitination. HECTD1 knockdown or ubiquitination repression intensified ECM degradation in IL‐1β‐stimulated chondrocytes. Taken together, low expression of HECTD1 repressed AURKA ubiquitination to elevate AURKA protein level and subsequently facilitated eIF4E‐mediated cap‐dependent translation of ADAMTS12, thus resulting in ECM degradation during OA progression.