ESPE Abstracts

Background and aims: Folate and vitamin B12 are methyl donors (MD) needed for the synthesis of methionine, which is the precursor of S-adenosylmethionine (SAM), the substrate of methylation in epigenetic, and epigenomic pathways. Low dietary intakes of folate and vitamin B12 are frequent, especially in pregnant women and in the elderly, and deficiency constitutes a risk factor for various diseases. The MD deficiency (MDD) leads to a decrease in SAM:SAH (S-adenosylhomocysteine) ratio and hyperhomocysteinemia, which has been related to osteoporosis and disruption of normal development of epiphyseal cartilage in rats by mechanisms that remain elusive.

Method: We studied the consequences of MDD on proliferation and differentiation of pre-osteoblasts in vitro using the human osteosarcoma cells, MG-63.

Results: The deprived cells showed a decreased expression of SIRT1 and PRMT1, PGC-1α and decreased SAM:SAH ratio, and increased expression of ERRα. Moreover, the MDD cells had an impaired response to treatment by 1,25(OH)₂ vitamin D with a decrease in alkaline phosphatase activity and a strong expression of adipocyte markers FABP4 and PPAR-λ indicating a disrupted osteoblast differentiation. These changes were explained by an imbalanced activation of PGC-1α, leading to its hypomethylation and hyperacetylation, through decreased expression of SIRT1 and PRMT1 and decreased SAM:SAH ratio, and by increased expression of ERRα.

Conclusion: Our data suggest that downregulation of PGC-1α would be a key factor in the deleterious effects of MDD on bone development. This link between methyl donor deficiency and epigenomic deregulations opens new insights into the pathogenesis of bone disease, in particular, in relation to the fetal programming hypothesis.