Wang Feng-Sheng, Lian Wei-Shiung, Lee Mel S, Weng Wen-Tsan, Huang Ying-Hsien, Chen Yu-Shan, Sun Yi-Chih, Wu Shing-Long, Chuang Pei-Chin, Ko Jih-Yang
Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung District, Kaohsiung, 83303, Taiwan.
Core Laboratory for Phenomics and Diagonistics, Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung District, Kaohsiung, 83303, Taiwan.
J Mol Med (Berl). 2017 May;95(5):499-512. doi: 10.1007/s00109-017-1512-x. Epub 2017 Jan 27.
Excess glucocorticoid administration impairs osteogenic activities, which raises the risk of osteoporotic disorders. Epigenetic methylation of DNA and histone regulates the lineage commitment of progenitor cells. This study was undertaken to delineate the actions of histone lysine demethylase 6a (UTX) with regard to the glucocorticoid impediment of osteogenic differentiation. Osteogenic progenitor cells responded to supraphysiological glucocorticoid by elevating CpG dinucleotide methylation proximal to transcription start sites within Runx2 and osterix promoters and Wnt inhibitor Dickkopf-1 (Dkk1) expression concomitant with low UTX expression. 5'-Aza-deoxycystidine demethylation of Runx2 and osterix promoters abolished the glucocorticoid inhibition of mineralized matrix accumulation. Gain of UTX function attenuated the glucocorticoid-induced loss of osteogenic differentiation, whereas UTX silencing escalated adipogenic gene expression and adipocyte formation. UTX sustained osteogenic gene transcription through maintaining its occupancy to Runx2 and osterix promoters. It also mitigated the trimethylation of histone 3 at lysine 27 (H3K27me3), which reduced H3K27me3 enrichment to Dkk1 promoter and thereby lowered Dkk1 transcription. Modulation of β-catenin and Dkk1 actions restored UTX signaling in glucocorticoid-stressed cells. In vivo, UTX inhibition by exogenous methylprednisolone and GSK-J4 administration, an effect that disturbed H3K27me3, β-catenin, Dkk1, Runx2, and osterix levels, exacerbated trabecular microarchitecture loss and marrow adiposity. Taken together, glucocorticoid reduction of UTX function hindered osteogenic differentiation. Epigenetic hypomethylation of osteogenic transcription factor promoters and H3K27 contributed to the UXT alleviation of Dkk1 transcription and osteogenesis in glucocorticoid-stressed osteogenic progenitor cells. Control of UTX action has an epigenetic perspective of curtailing glucocorticoid impairment of osteogenic differentiation and bone mass.
UTX attenuates glucocorticoid deregulation of osteogenesis and adipogenesis. UTX reduces Runx2 promoter methylation and H3K27me3 enrichment in the Dkk1 promoter. β-catenin and Dkk1 modulate the glucocorticoid inhibition of UTX signaling. UTX inhibition exacerbates bone mass, trabecular microstructure and fatty marrow. UTX signaling is indispensable in fending off glucocorticoid-impaired osteogenesis.
过量给予糖皮质激素会损害成骨活性，从而增加骨质疏松症的发病风险。DNA和组蛋白的表观遗传甲基化调节祖细胞的谱系定向。本研究旨在阐明组蛋白赖氨酸去甲基化酶6a（UTX）在糖皮质激素对成骨分化的抑制作用中的作用。成骨祖细胞通过提高Runx2和osterix启动子转录起始位点附近的CpG二核苷酸甲基化以及Wnt抑制剂Dickkopf-1（Dkk1）的表达，同时降低UTX表达，来响应超生理剂量的糖皮质激素。Runx2和osterix启动子的5'-氮杂-脱氧胞苷去甲基化消除了糖皮质激素对矿化基质积累的抑制作用。UTX功能的增强减弱了糖皮质激素诱导的成骨分化丧失，而UTX沉默则增强了脂肪生成基因的表达和脂肪细胞的形成。UTX通过维持其在Runx2和osterix启动子上的占据来维持成骨基因转录。它还减轻了组蛋白3赖氨酸27（H3K27me3）的三甲基化，从而减少了H3K27me3在Dkk1启动子上的富集，进而降低了Dkk1的转录。β-连环蛋白和Dkk1作用的调节恢复了糖皮质激素应激细胞中的UTX信号。在体内，外源性甲基泼尼松龙和GSK-J4给药抑制UTX，这种作用扰乱了H3K27me3、β-连环蛋白、Dkk1、Runx2和osterix的水平，加剧了小梁微结构的丧失和骨髓脂肪化。综上所述，糖皮质激素降低UTX功能阻碍了成骨分化。成骨转录因子启动子和H3K27的表观遗传低甲基化有助于UTX减轻糖皮质激素应激的成骨祖细胞中Dkk1的转录和成骨作用。控制UTX的作用从表观遗传学角度减少了糖皮质激素对成骨分化和骨量的损害。
UTX减轻糖皮质激素对成骨和脂肪生成的失调。UTX减少Runx2启动子甲基化和Dkk1启动子中的H3K27me3富集。β-连环蛋白和Dkk1调节糖皮质激素对UTX信号的抑制。抑制UTX会加剧骨量、小梁微结构和脂肪骨髓的变化。UTX信号在抵御糖皮质激素损害的成骨过程中不可或缺。
