No abstract

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 D3 (1,25(OH)2D3) 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)2D3 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)2D3 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)2D3. Bisulfite DNA pyrosequencing reveals 1,25(OH)2D3 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)2D3 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)2D3 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)2D3-induced transcriptional repression of BMP2 involves DNA methylation and histone modification. The study provides novel evidence that 1,25(OH)2D3 represses bone formation through down-regulating BMP2 expression both in vivo and in vitro.

While uncommon, post-traumatic pelvic malunions present reconstructive challenges and are associated with significant disability and financial burden. A transiliac osteotomy is a surgical technique useful to correct certain types of pelvic fracture malunions, and is only used when the correction of a limb-length discrepancy is the primary goal. This study aims to present our experience with this technique in the treatment of post-traumatic pelvic malunions.Eight patients who underwent transiliac osteotomies for post-traumatic pelvic malunions at our department from 2006 to 2011 were included in this study. We reviewed the clinical and radiographic results of these patients.By the time of their last follow-up, all osteotomy sites and iliac bone graft had healed with no evidence of internal fixation failure. Of the 3 patients who complained of preoperative posterior pain, 2 reported an improvement. All 8 patients noted the resolution of their lower back pain. At the time of their final follow-up, 4 patients could walk normally, 2 had a slight limp without a cane, 1 patient used a cane to help with standing and walking, and the final felt limited during ambulation with a cane. Limb-lengthening relative to preoperative measurements was 2.86 cm (2.2–3.0 cm) at the time of the last follow-up. Two patients were able to return to their previous jobs, 4 patients changed their jobs or engaged in light manual labor while the final 2 were able to perform activities of daily living but were unable to participate in work or labor. Three patients reported being “extremely satisfied” with their outcomes, 3 were “satisfied,” and 2 were “unsatisfied.”A transiliac osteotomy can be used to manage selected cases of post-traumatic pelvic malunions that are unable to be corrected with a traditional release and osteotomy. However, in these cases the correction of limb-length discrepancies should be the primary reconstructive goal.