Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, China.
Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, China.
Biochem Biophys Res Commun. 2019 Sep 24;517(3):491-498. doi: 10.1016/j.bbrc.2019.07.095. Epub 2019 Jul 31.
Dexamethasone (DEX) induces significant cytotoxicity to human osteoblasts. cPWWP2A is recently-indentified novel circular RNA (circRNA), acting as an endogenous sponge of microRNA-579 (miR-579). The present study tested the expression and potential functions of the cPWWP2A-miR-579 axis in DEX-treated osteoblasts. We show that cPWWP2A is downregulated in the necrotic femoral head tissues of DEX-taking human patients as well as in DEX-treated human osteoblasts. In OB-6 osteoblastic cells and primary human osteoblasts ectopic overexpression of cPWWP2A potently inhibited DEX-induced miR-579 accumulation, cell death, apoptosis and programmed necrosis. Silencing miR-579, by targeted siRNAs, also attenuated DEX-induced cytotoxicity in human osteoblasts. Significantly, mimicking DEX-induced actions, cPWWP2A silencing or forced miR-579 overexpression induced significant cytotoxicity in human osteoblasts. Further analyses demonstrated that miR-579's targets, including SIRT1 and PDK1 (phosphoinositide-dependent protein kinase 1), were downregulated in DEX-treated osteoblasts. Their levels were decreased as well in the necrotic femoral head tissues of DEX-taking human patients. Taken together we show that dysregulation of the cPWWP2A-miR-579 axis is involved in DEX-induced cytotoxicity in human osteoblasts.
地塞米松（DEX）可诱导人成骨细胞产生显著的细胞毒性。cPWWP2A 是最近鉴定出的新型环状 RNA（circRNA），作为 microRNA-579（miR-579）的内源性海绵。本研究检测了 cPWWP2A-miR-579 轴在 DEX 处理的成骨细胞中的表达和潜在功能。我们表明，cPWWP2A 在接受 DEX 治疗的人类患者的坏死性股骨头组织以及在 DEX 处理的人成骨细胞中下调。在 OB-6 成骨细胞和原代人成骨细胞中，cPWWP2A 的异位过表达可强烈抑制 DEX 诱导的 miR-579 积累、细胞死亡、凋亡和程序性坏死。通过靶向 siRNAs 沉默 miR-579 也可减轻人成骨细胞中 DEX 诱导的细胞毒性。重要的是，模拟 DEX 诱导的作用，cPWWP2A 沉默或强制过表达 miR-579 可在人成骨细胞中引起显著的细胞毒性。进一步的分析表明，miR-579 的靶标，包括 SIRT1 和 PDK1（磷酸肌醇依赖性蛋白激酶 1），在 DEX 处理的成骨细胞中下调。它们在接受 DEX 治疗的人类患者的坏死性股骨头组织中也减少了。综上所述，我们表明 cPWWP2A-miR-579 轴的失调参与了 DEX 诱导的人成骨细胞毒性。
