Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, China.
Department of Sports Injury, Xi'an Honghui Hospital, Xi'an, China.
Cell Mol Life Sci. 2022 Jul 8;79(8):405. doi: 10.1007/s00018-022-04427-7.
Osteoarthritis (OA) is mainly characterized by articular cartilage degeneration, synovial fibrosis, and inflammation. LncRNA CRNDE (colorectal neoplasia differentially expressed) has been reported to be down-regulated in age-related OA, but its role in injury-induced OA needs to be further explored. In this study, an OA rat model was established using anterior cruciate ligament transection, and the adenovirus-mediated CRNDE overexpression (Ad-CRNDE) or DACT1 (dapper antagonist of catenin-1) interference (sh-DACT1) vectors were administered by intraarticular injection. Moreover, chondrocyte‑like ATDC5 cells were treated with IL-1β (10 ng/mL) to simulate OA conditions in vitro. We found that overexpression of CRNDE alleviated cartilage damage and synovitis in OA rats, and suppressed IL-1β-induced apoptosis, inflammation, and extracellular matrix (ECM) degradation in chondrocyte‑like ATDC5 cells, while silencing DACT1 effectively antagonized the protective effect of CRNDE both in vivo and in vitro. Mechanism studies revealed that DACT1 could act as a downstream target of CRNDE. By recruiting p300, CRNDE promoted the enrichment of H3K27ac in the DACT1 promoter, thus promoting DACT1 transcription. In addition, CRNDE hindered the activation of the Wnt/β-catenin pathway in IL-1β-stimulated cells by inducing DACT1 expression. In conclusion, CRNDE promoted DACT1 expression through epigenetic modification and restrained the activation of Wnt/β-catenin signaling to impede the progression of OA.
骨关节炎（OA）主要表现为关节软骨退变、滑膜纤维化和炎症。长链非编码 RNA CRNDE（结直肠肿瘤差异表达）在与年龄相关的 OA 中被报道下调，但它在损伤诱导的 OA 中的作用需要进一步探索。在这项研究中，通过前交叉韧带切断术建立了 OA 大鼠模型，并通过关节内注射腺病毒介导的 CRNDE 过表达（Ad-CRNDE）或 DACT1（连环蛋白-1 的 Dapper 拮抗剂）干扰（sh-DACT1）载体进行干预。此外，用白细胞介素-1β（10ng/ml）处理软骨细胞样 ATDC5 细胞以模拟 OA 体外条件。我们发现，CRNDE 的过表达减轻了 OA 大鼠的软骨损伤和滑膜炎，并抑制了 IL-1β诱导的软骨细胞样 ATDC5 细胞凋亡、炎症和细胞外基质（ECM）降解，而沉默 DACT1 有效地拮抗了 CRNDE 在体内和体外的保护作用。机制研究表明，DACT1 可以作为 CRNDE 的下游靶标。CRNDE 通过募集 p300，促进 DACT1 启动子中 H3K27ac 的富集，从而促进 DACT1 转录。此外，CRNDE 通过诱导 DACT1 表达，抑制了 IL-1β 刺激细胞中 Wnt/β-catenin 通路的激活。总之，CRNDE 通过表观遗传修饰促进 DACT1 的表达，并抑制 Wnt/β-catenin 信号通路的激活，从而阻碍 OA 的进展。
