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BackgroundDNA methylation is a key epigenetic mechanism for driving and stabilizing cell-fate decisions. Local deposition and removal of DNA methylation are tightly coupled with transcription factor binding, although the relationship varies with the specific differentiation process. Conversion of monocytes to osteoclasts is a unique terminal differentiation process within the hematopoietic system. This differentiation model is relevant to autoimmune disease and cancer, and there is abundant knowledge on the sets of transcription factors involved.ResultsHere we focused on DNA methylation changes during osteoclastogenesis. Hypermethylation and hypomethylation changes took place in several thousand genes, including all relevant osteoclast differentiation and function categories. Hypomethylation occurred in association with changes in 5-hydroxymethylcytosine, a proposed intermediate toward demethylation. Transcription factor binding motif analysis revealed an over-representation of PU.1, NF-κB, and AP-1 (Jun/Fos) binding motifs in genes undergoing DNA methylation changes. Among these, only PU.1 motifs were significantly enriched in both hypermethylated and hypomethylated genes; ChIP-seq data analysis confirmed its association to both gene sets. Moreover, PU.1 interacts with both DNMT3b and TET2, suggesting its participation in driving hypermethylation and hydroxymethylation-mediated hypomethylation. Consistent with this, siRNA-mediated PU.1 knockdown in primary monocytes impaired the acquisition of DNA methylation and expression changes, and reduced the association of TET2 and DNMT3b at PU.1 targets during osteoclast differentiation.ConclusionsThe work described here identifies key changes in DNA methylation during monocyte-to-osteoclast differentiation and reveals novel roles for PU.1 in this process.

Studies that evaluate the influence of gastric bypass (RYGP) on bone mass are limited to short-term follow-up. We analysed changes in bone mineral density (BMD) three years after surgery and evaluated the main determinants of the development of bone disease. Prospective study of 59 morbidly obese white women aged 46 ± 8 years. BMD scanning using DEXA and plasma determinations of calcium, parathyroid hormone, 25-hydroxyvitamin D and insulin-like growth factor-I were made prior, at 12 months and 3 years after surgery. In the first postoperative year BMD decreased at femoral neck (FN) 10.2 % and in the lumbar spine (LS) 3.2 %, in the third year it additionally decreased 2.7 % and 3.1 %, respectively. BMD at both sites remained above the values of women of the same age. In the follow-up, 1.7 % developed osteoporosis at FN and 6.8 % at LS. Patients with bone disease were older, the percentage of women with menopause was greater in this group and had lower initial and final values of lean mass. The percentage of BMD loss at FN remained positively associated with the percentage of lean mass loss [β 0.304, p=0.045], and menopause [β 0.337, p=0.025]. Major osteoporotic fracture and hip fracture risk was low even in menopausal patients (3.1 % and 0.40 %, respectively). After RYGP menopausal women and those with greater lean mass loss are at higher risk of BMD loss but progression to osteoporosis is uncommon and the risk of fracture is low.

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