Enhancer of Zeste Homolog 2 and Histone Deacetylase 9c Regulate Age‐Dependent Mesenchymal Stem Cell Differentiation into Osteoblasts and Adipocytes

• Published in: Stem cells (Dayton, Ohio) Ohio), 2016-08, Vol.34 (8), p.2183-2193
• Main Authors: Chen, Ya‐Huey, Chung, Chiao‐Chen, Liu, Yu‐Chia, Yeh, Su‐Peng, Hsu, Jennifer L., Hung, Mien‐Chie, Su, Hong‐Lin, Li, Long‐Yuan
• Format: Article
• Language: English
• Subjects: Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; Adipogenesis; Adolescent; Adult; Age; Aged; Aged, 80 and over; Aging; Aging - metabolism; Animals; Attenuation; Biocompatibility; Bone loss; Catalysis; Cell Differentiation; Child; Deactivation; Differentiation (biology); Disruption; Enhancer of Zeste Homolog 2 Protein - metabolism; EZH2; Feasibility; Gene Knockdown Techniques; Genes; HDAC9c; Histone deacetylase; Histone Deacetylases - metabolism; Homology; Humans; Inactivation; Intervention; Mesenchymal stem cells; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - metabolism; Mesenchyme; Mice; Middle Aged; Models, Biological; Obesity; Origins; Osteoblastogenesis; Osteoblasts; Osteoblasts - cytology; Osteoblasts - metabolism; Osteogenesis; Osteoporosis; Polycomb group proteins; Repressor Proteins - metabolism; Stem cell transplantation; Stem cells; Young Adult
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2400

Mesenchymal stem cells (MSCs) are multipotent precursors that can undergo multilineage differentiation, including osteogenesis and adipogenesis, which are two mutually exclusive events. Previously, we demonstrated that enhancer of zeste homolog 2 (EZH2), the catalytic component of the Polycomb‐repressive complex 2, mediates epigenetic silencing of histone deacetylase 9c (HDAC9c) in adipocytes but not in osteoblasts and that HDAC9c accelerates osteogenesis while attenuating adipogenesis of MSCs through inactivation of peroxisome proliferator‐activated receptor gamma 2 activity. Importantly, disrupting the balance between adipogenesis and osteogenesis can lead to age‐associated bone loss (osteoporosis) and obesity. Here, we investigated the relationship between age, and osteogenic and adipogenic differentiation potential of MSCs by comparing EZH2 and HDAC9c expression in osteoblasts and adipocytes of both human and mice origins to determine whether the EZH2‐HDAC9c axis regulates age‐associated osteoporosis and obesity. Our findings indicated that a decline in HDAC9c expression over time was accompanied by increased EZH2 expression and suggested that a therapeutic intervention for age‐associated osteoporosis and obesity may be feasible by targeting the EZH2‐HDAC9c axis. Stem Cells 2016;34:2183–2193 EZH2 and HDAC9c regulate age‐dependent mesenchymal stem cell differentiation into osteoblasts and adipocytes. Lower expression of EZH2 in young MSCs promotes expression of HDAC9c, which sequesters PPARγ‐2 and allows RUNX2 to turn on OPN transcription, leading to increased osteogenesis. Inversely, higher expression of EZH2 in aged MSCs suppresses HDAC9c, allowing PPARγ‐2 to turn on transcription of FABP4, which enhances adipogenesis.