Tao Tao, Zhang Yunkun, Wei Hui, Heng Ke
Department of Orthopedics, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China.
Biosci Biotechnol Biochem. 2021 Feb 24;85(3):545-552. doi: 10.1093/bbb/zbaa105.
Interleukin-1 receptor-associated kinase-3 (IRAK3) has a distinctive role in regulating inflammation. However, the functional role of IRAK3 and regulatory mechanism underlying the pathogenesis of osteoarthritis (OA) remain unclear. Here, we first found that IRAK3 was upregulated, while miR-33b-3p was downregulated in the cartilage of OA patients and IL-1β-induced CHON-001 cells. IRAK3 was confirmed as the direct target of miR-33b-3p and negatively regulated by miR-33b-3p. There was an inverse correlation between IRAK3 mRNA expression and miR-33b-3p expression in OA cartilage tissues. The in vitro functional experiments showed that miR-33b-3p overexpression caused a remarkable increase in viability, a significant decrease in inflammatory mediators (IL-1β and TNF-α), and apoptosis in IL-1β-induced CHON-001 cells. Importantly, IRAK3 knockdown imitated, while overexpression reversed the effects of miR-33b-3p on IL-1β-induced inflammation and apoptosis in CHON-001 cells. Collectively, miR-33b-3p significantly alleviated IL-1β-induced inflammation and apoptosis by downregulating IRAK3, which may serve as a promising target for OA.
白细胞介素-1受体相关激酶-3（IRAK3）在调节炎症中具有独特作用。然而，IRAK3在骨关节炎（OA）发病机制中的功能作用及调控机制仍不清楚。在此，我们首先发现，在OA患者软骨组织及白细胞介素-1β（IL-1β）诱导的CHON-001细胞中，IRAK3表达上调，而miR-33b-3p表达下调。IRAK3被证实为miR-33b-3p的直接靶标，并受到miR-33b-3p的负调控。在OA软骨组织中，IRAK3 mRNA表达与miR-33b-3p表达呈负相关。体外功能实验表明，miR-33b-3p过表达可使IL-1β诱导的CHON-001细胞活力显著增加，炎症介质（IL-1β和肿瘤坏死因子-α（TNF-α））显著减少，凋亡增加。重要的是，敲低IRAK3可模拟，而过表达则可逆转miR-33b-3p对IL-1β诱导的CHON-001细胞炎症和凋亡的影响。总体而言，miR-33b-3p通过下调IRAK3显著减轻IL-1β诱导的炎症和凋亡，这可能成为OA的一个有前景的治疗靶点。
