Osteogenic differentiation plays important roles in the pathogenesis of
osteoporosis. In this study, we explored the regulatory mechanism of
histone methyltransferase SET domain bifurcated 1 (SETDB1) underlying the osteogenic differentiation in
osteoporosis. The common
osteoporosis-related genes were retrieved from the GeneCards, CTD, and Phenolyzer databases. The enrichment analysis was conducted on the candidate
osteoporosis-related genes using the PANTHER software, and the binding site between
transcription factors and target genes predicted by hTFtarget. The bioinformatics analyses suggested 6
osteoporosis-related
chromatin/
chromatin binding protein or regulatory
proteins (HDAC4,
SIRT1, SETDB1, MECP2, CHD7, and DKC1). Normal and
osteoporosis tissues were collected from
osteoporosis patients to examine the expression of SETDB1. It was found that SETDB1 was poorly expressed in osteoporotic femoral tissues, indicating that SETDB1 might be involved in the development of
osteoporosis. We induced SETDB1 overexpression/knockdown, orthodenticle homeobox 2 (OTX2) overexpression, activation of Wnt/β-
catenin or BMP-Smad pathways alone or in combination in osteoblasts or ovariectomized mice. The data indicated that SETDB1 methylation regulated H3K9me3 in the OTX2 promoter region and inhibited the expression of OTX2. Besides, the BMP-Smad and Wnt/β-
catenin pathways were inhibited by OTX2, thereby resulting in inhibited osteogenic differentiation. Animal experiments showed that overexpressed SETDB1 could promote the increase of
calcium level and differentiation of femoral tissues. In conclusion, upregulation of SETDB1 promotes osteogenic differentiation by inhibiting OTX2 and activating the BMP-Smad and Wnt/β-
catenin pathways in
osteoporosis.