Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 77, Issue 12, Pages 2407-2421Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-019-03289-w
Keywords
Lysine demethylase 4A; Adipocyte; Osteoblast; Differentiation; Secreted frizzled-related protein 4; CCAAT; enhancer-binding protein alpha; Wnt; beta-catenin
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Funding
- National Natural Science Foundation of China [81871741, 81672116, 81772297] Funding Source: Medline
- Graduate student innovation fund of Tianjin Medical University [YJSCX201803] Funding Source: Medline
- Natural Science Foundation of Tianjin Municipal Science and Technology Commission [18JCZDJC32200, 18JCQNJC12900] Funding Source: Medline
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Epigenetic modifications play a central role in cell differentiation and development. In the current study, we have recognized lysine demethylase 4A (KDM4A) as a novel epigenetic regulator of osteoblast and adipocyte differentiation. Kdm4a expression was upregulated during osteogenesis and adipogenesis of primary marrow stromal cells and established stromal ST2 line. Overexpression of wild-type Kdm4a promoted adipogenic differentiation and blocked osteogenic differentiation of the progenitor cells. This effect was largely alleviated when the catalytically dead mutation was made. Conversely, depletion or inactivation of Kdm4a in undifferentiated progenitor cells inhibited the formation of adipocytes and promoted the differentiation of osteoblasts. Mechanism explorations showed that overexpression of Kdm4a upregulated the expression of secreted frizzled-related protein 4 (Sfrp4) and CCAAT/enhancer-binding protein alpha (C/ebp alpha). Chromatin immunoprecipitation assay demonstrated that KDM4A directly bound the promoters of Sfrp4 and C/ebp alpha, removed the histone methylation mark H3K9me3, and reduced DNA methylation levels of CpG in promoter regions of C/ebp alpha and Sfrp4. Furthermore, overexpression of Kdm4a inactivated canonical Wnt signaling. Moreover, activation of canonical Wnt signaling through silencing of Sfrp4 in ST2 attenuated the inhibition of osteogenic differentiation and the enhancement of adipogenic differentiation by KDM4A. These data have identified KDM4A as a novel regulator of osteoblast and adipocyte differentiation and suggest KDM4A inhibition as a potential therapeutic target for treating metabolic disorders such as osteoporosis.
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