Methyl donor deficiency impairs bone development via peroxisome proliferator-activated receptor-γ coactivator-1α-dependent vitamin D receptor pathway.
Fiche publication
Date publication
octobre 2016
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GUEANT Jean-Louis, Dr BATTAGLIA-HSU Shyue-Fang
Tous les auteurs :
Feigerlova E, Demarquet L, Melhem H, Ghemrawi R, Battaglia-Hsu SF, Ewu E, Alberto JM, Helle D, Weryha G, Guéant JL
Lien Pubmed
Résumé
Deficiency in methyl donor (folate and vitamin B12) and in vitamin D is independently associated with altered bone development. Previously, methyl donor deficiency (MDD) was shown to weaken the activity of nuclear receptor coactivator, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), for nuclear signaling in rat pups, including estrogen receptor-α and estrogen-related receptor-α; its effect on vitamin D receptor (VDR) signaling, however, is unknown. We studied bone development under MDD in rat pups and used human MG-63 preosteoblast cells to better understand the associated molecular mechanism. In young rats, MDD decreased total body bone mineral density, reduced tibia length, and impaired growth plate maturation, and in preosteoblasts, MDD slowed cellular proliferation. Mechanistic studies revealed decreased expression of VDR, estrogen receptor-α, PGC1α, arginine methyltransferase 1, and sirtuin 1 in both rat proximal diaphysis of femur and in MG-63, as well as decreased nuclear VDR-PGC1α interaction in MG-63 cells. The weaker VDR-PGC1α interaction could be attributed to the reduced protein expression, imbalanced PGC1α methylation/acetylation, and nuclear VDR sequestration by heat shock protein 90 (HSP90). These together compromised bone development, which is reflected by lowered bone alkaline phosphatase and increased proadipogenic peroxisome proliferator-activated receptor-γ, adiponectin, and estrogen-related receptor-α expression. Of interest, under MDD, the bone development effects of 1,25-dihydroxyvitamin D3 were ineffectual and these could be rescued by the addition of S-adenosylmethionine, which restored expression of arginine methyltransferase 1, PGC1α, adiponectin, and HSP90. In conclusion, MDD inactivates vitamin D signaling via both disruption of VDR-PGC1α interaction and sequestration of nuclear VDR attributable to HSP90 overexpression. These data suggest that vitamin D treatment may be ineffective under MDD.-Feigerlova, E., Demarquet, L., Melhem, H., Ghemrawi, R., Battaglia-Hsu, S.-F., Ewu, E., Alberto, J.-M., Helle, D., Weryha, G., Guéant, J.-L. Methyl donor deficiency impairs bone development via peroxisome proliferator-activated receptor-γ coactivator-1α-dependent vitamin D receptor pathway.
Référence
FASEB J.. 2016 Oct;30(10):3598-3612