State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China.
Cell Death Dis. 2018 Feb 7;9(2):176. doi: 10.1038/s41419-017-0231-0.
Disrupted Wnt signaling in osteoblastic-lineage cells leads to bone formation defect in osteoporosis. However, the factors repressing Wnt signaling are unclear. In our study, we found that Wnt signaling was suppressed persistently in bone marrow-derived mesenchymal stem cells (BMSCs) during osteoporosis. Accordingly, histone acetylation levels on Wnt genes (Wnt1, Wnt6, Wnt10a, and Wnt10b) were declined in BMSCs from OVX mice. By screening the family of histone acetyltransferase, we identified that GCN5 expression increased during osteogenic differentiation of BMSCs, whereas decreased after osteoporosis. Further analysis revealed that GCN5 promoted osteogenic differentiation of BMSCs by increasing acetylation on histone 3 lysine 9 loci on the promoters of Wnt genes. Reduced GCN5 expression suppressed Wnt signaling, resulting in osteogenic defect of BMSCs from OVX mice. Moreover, restoring GCN5 levels recovered BMSC osteogenic differentiation, and attenuated bone loss in OVX mice. Taken together, our study demonstrated that disrupted histone acetylation modification in BMSCs lead to bone formation defect during osteoporosis. The findings also introduced a novel therapeutic target for osteoporosis.
成骨细胞谱系细胞中 Wnt 信号的紊乱导致骨质疏松症中的骨形成缺陷。然而，抑制 Wnt 信号的因素尚不清楚。在我们的研究中，我们发现骨质疏松症期间骨髓间充质干细胞（BMSCs）中的 Wnt 信号持续受到抑制。相应地，OVX 小鼠 BMSCs 中 Wnt 基因（Wnt1、Wnt6、Wnt10a 和 Wnt10b）上的组蛋白乙酰化水平下降。通过筛选组蛋白乙酰转移酶家族，我们发现 GCN5 在 BMSCs 的成骨分化过程中表达增加，而在骨质疏松症后减少。进一步分析表明，GCN5 通过增加 Wnt 基因启动子上组蛋白 3 赖氨酸 9 位的乙酰化来促进 BMSCs 的成骨分化。减少 GCN5 的表达抑制了 Wnt 信号，导致 OVX 小鼠 BMSCs 的成骨缺陷。此外，恢复 GCN5 水平可恢复 BMSC 的成骨分化，并减轻 OVX 小鼠的骨质流失。总之，我们的研究表明，BMSCs 中组蛋白乙酰化修饰的紊乱导致骨质疏松症期间的骨形成缺陷。研究结果还为骨质疏松症提供了一个新的治疗靶点。
