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Genetic hypercalciuric stone-forming (GHS) rats have increased intestinal Ca absorption, decreased renal tubule Ca reabsorption and low bone mass, all of which are mediated at least in part by elevated tissue levels of the vitamin D receptor (VDR). Both 1,25-dihydroxyvitamin D 3  (1,25(OH) 2 D 3 ) and bone morphogenetic protein 2 (BMP2) are critical for normal maintenance of bone metabolism and bone formation, respectively. The complex nature of bone cell regulation suggests a potential interaction of these two important regulators in GHS rats. In the present study,  BMP2  expression is suppressed by the VDR-1,25(OH) 2 D 3  complex in Bone Marrow Stromal Cells (BMSCs) from GHS and SD rat and in UMR-106 cell line. We used chromatin immunoprecipitation (ChIP) assays to identify VDR binding to only one of several potential binding sites within the  BMP2  promoter regions. This negative region also mediates suppressor reporter gene activity. The molecular mechanisms underlying the down-regulation of  BMP2  by 1,25(OH) 2 D 3  were studied in vitro in BMSCs and UMR-106 cells using the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) and the histone deacetylase inhibitor trichostatin A (TSA). Both DAC and TSA activate  BMP2  expression in combination with 1,25(OH) 2 D 3 . Bisulfite DNA pyrosequencing reveals 1,25(OH) 2 D 3  to completely hypermethylate a single CpG site in the same  BMP2  promoter region identified by the ChIP and reporter gene assays. ChIP assays also show that 1,25(OH) 2 D 3  can increase the repressive histone mark H3K9me2 and reduce the acetylation of histone H3 at the same  BMP2  promoter region. Taken together, our results indicate that 1,25(OH) 2 D 3  binding to VDR down-regulates  BMP2  gene expression in BMSCs and osteoblast-like UMR-106 cells by binding to the  BMP2  promoter region. The mechanism of this 1,25(OH) 2 D 3 -induced transcriptional repression of  BMP2  involves DNA methylation and histone modification. The study provides novel evidence that 1,25(OH) 2 D 3  represses bone formation through down-regulating  BMP2  expression both in vivo and in vitro.

Epigenetic Regulation of BMP2 by 1,25-dihydroxyvitamin D3 through DNA Methylation and Histone Modification