长链非编码 RNA HOTAIR 通过抑制 WIF-1 的表达和激活 Wnt 通路促进骨关节炎软骨降解。

A long non-coding RNA, HOTAIR, promotes cartilage degradation in osteoarthritis by inhibiting WIF-1 expression and activating Wnt pathway.

机构信息

Department of Orthopaedics, Tianjin Hospital, Tianjin, 300211, China.

Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, 100044, China.

出版信息

BMC Mol Cell Biol. 2020 Jul 10;21(1):53. doi: 10.1186/s12860-020-00299-6.

BACKGROUND

Long noncoding RNAs (lncRNAs) are recently found to be critical regulators of the epigenome. However, our knowledge of their role in osteoarthritis (OA) development is limited. This study investigates the mechanism by which HOTAIR, a key lncRNA with elevated expression in OA, affects OA disease progression.

RESULTS

HOTAIR expression was greatly elevated in osteoarthritic compared to normal chondrocytes. Silencing and over-expression of HOTAIR in SW1353 cells respectively reduced and increased the expression of genes associated with cartilage degradation in OA. Investigation of molecular pathways revealed that HOTAIR acted directly on Wnt inhibitory factor 1 (WIF-1) by increasing histone H3K27 trimethylation in the WIF-1 promoter, leading to WIF-1 repression that favours activation of the Wnt/β-catenin pathway.

CONCLUSIONS

Activation of Wnt/β-catenin signalling by HOTAIR through WIF-1 repression in osteoarthritic chondrocytes increases catabolic gene expression and promotes cartilage degradation. This is the first study to demonstrate a direct link between HOTAIR, WIF-1 and OA progression, which may be useful for future investigations into disease biomarkers or therapeutic targets.

背景

长链非编码 RNA（lncRNA）最近被发现是表观基因组的关键调节因子。然而，我们对其在骨关节炎（OA）发展中的作用的了解有限。本研究探讨了 HOTAIR（OA 中表达上调的关键 lncRNA）影响 OA 疾病进展的机制。

结果

OA 软骨细胞中 HOTAIR 的表达明显升高。SW1353 细胞中 HOTAIR 的沉默和过表达分别降低和增加了与 OA 软骨降解相关的基因的表达。对分子途径的研究表明，HOTAIR 通过增加 WIF-1 启动子上的组蛋白 H3K27 三甲基化，直接作用于 Wnt 抑制因子 1（WIF-1），从而抑制 WIF-1，有利于 Wnt/β-catenin 通路的激活。