Department of Spine Surgery, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha, 410008, China.
Clin Epigenetics. 2019 Jul 23;11(1):107. doi: 10.1186/s13148-019-0706-1.
Idiopathic scoliosis (IS) is a complex disease with an unclear etiology, and the worldwide prevalence is approximately 2-3%. As an important link between environmental factors and phenotypic differences, epigenetic changes, such as lncRNA, miRNA, and DNA methylation, have recently been reported to be associated with the development of IS. However, the correlation between histone methylation, another classical epigenetic mechanism, and IS has not been determined. In this study, we investigated the morphological changes, alterations in the levels of histone methylation, and cell proliferation-related pathway in inferior facet joint cartilage in 11 IS patients and 10 comparable controls.
Compared with the control group, narrowed facet joint cartilage but increased proliferative chondrocytes and upregulated collagen type II (COL2A1) and B-cell lymphoma-2 (Bcl2) were observed in IS patients. Additionally, tri-methylation levels of H3K9 (H3K9me3) rather than other lysine sites were significantly increased in IS patients, coinciding with the upregulation of its specific enzyme, suppressor of variegation 3-9, drosophila homolog of 1 (SUV39H1). In addition, Bcl2-targeted miR-15a was downregulated in IS patients, and the level of H3K9me3 in the promoter region of the miR-15a host gene was remarkably increased in IS patients compared with the control group. Moreover, overexpressing SUV39H1 in ATDC5 cells with increased H3K9me3 levels led to similar changes, with increased expression of COL2A1 and Bcl2, decreased expression of miR-15a, and increased cell proliferation.
Thus, our study suggests that increased chondrocyte proliferation occurs in the facet joint cartilage of IS patients compared with the control group and may be promoted by the elevated levels of H3K9me3 and SUV39H1, which regulate the miR-15a/Bcl2 pathway. This dysregulation of chondrocyte proliferation could result in abnormal spinal growth and may additionally participate in the development and progression of IS.
特发性脊柱侧凸（IS）是一种病因不明的复杂疾病，全球患病率约为 2-3%。作为环境因素与表型差异之间的重要环节，表观遗传变化，如长链非编码 RNA（lncRNA）、微小 RNA（miRNA）和 DNA 甲基化，最近被报道与 IS 的发生有关。然而，另一种经典的表观遗传机制——组蛋白甲基化与 IS 之间的相关性尚未确定。在这项研究中，我们研究了 11 例 IS 患者和 10 例可比对照组下关节突软骨的形态变化、组蛋白甲基化水平的改变以及与细胞增殖相关的通路。
与对照组相比，IS 患者的关节突软骨变窄，但增殖性软骨细胞增多，II 型胶原（COL2A1）和 B 细胞淋巴瘤-2（Bcl2）表达上调。此外，IS 患者 H3K9 三甲基化（H3K9me3）水平而非其他赖氨酸位点明显升高，与特异性酶 SUV39H1 抑制物 3-9，果蝇同源物 1（SUV39H1）的上调相一致。此外，IS 患者中 Bcl2 靶向的 miR-15a 下调，与对照组相比，IS 患者 miR-15a 宿主基因启动子区域的 H3K9me3 水平显著升高。此外，在 ATDC5 细胞中过表达 SUV39H1 导致 H3K9me3 水平升高，导致 COL2A1 和 Bcl2 表达增加、miR-15a 表达降低、细胞增殖增加等类似变化。
因此，我们的研究表明，与对照组相比，IS 患者的关节突软骨中软骨细胞增殖增加，并且可能是由 H3K9me3 和 SUV39H1 水平升高促进的，这两者调节 miR-15a/Bcl2 通路。这种软骨细胞增殖的失调可能导致脊柱生长异常，并可能进一步参与 IS 的发生和发展。
