Impaired autophagy triggered by HDAC9 in mesenchymal stem cells accelerates bone mass loss

作者：Liqiang Zhang, Meng Qi, Ji Chen, Jiangdong Zhao, Liya Li, Jiachen Hu, Yan Jin, Wenjia Liu · 发表于：Stem Cell Research & Therapy · 年份：2020 · DOI：10.1186/s13287-020-01785-6 · 被引用次数：41 · 研究领域：Autophagy in Disease and Therapy、Histone Deacetylase Inhibitors Research、Bone Metabolism and Diseases

BACKGROUND: Bone mass loss in aging is linked with imbalanced lineage differentiation of bone marrow mesenchymal stem cells (BMMSCs). Recent studies have proved that histone deacetylases (HDACs) are regarded as key regulators of bone remodeling. However, HDACs involve in regulating BMMSC bio-behaviors remain elusive. Here, we investigated the ability of HDAC9 on modulation of autophagy and its significance in lineage differentiation of BMMSCs. METHODS: The effects of HDAC9 on lineage differentiation of BMMSCs and autophagic signaling were assessed by various biochemical (western blot and ChIP assay), morphological (TEM and confocal microscopy), and micro-CT assays. RESULTS: Sixteen-month mice manifested obvious bone mass loss and marrow fat increase, accompanied with decreased osteogenic differentiation and increased adipogenic differentiation of BMMSCs. Further, the expression of HDAC9 elevated in bone and BMMSCs. Importantly, HDAC9 inhibitors recovered the lineage differentiation abnormality of 16-month BMMSCs and reduced p53 expression. Mechanistically, we revealed that HDAC9 regulated the autophagy of BMMSCs by controlling H3K9 acetylation in the promoters of the autophagic genes, ATG7, BECN1, and LC3a/b, which subsequently affected their lineage differentiation. Finally, HDAC9 inhibition improved endogenous BMMSC properties and promoted the bone mass recovery of 16-month mice. CONCLUSIONS: Our data demonstrate that HDAC9 is a key regulator in a variety of bone mass by re...