title: Methyl donor deficiency impairs bone development via peroxisome proliferator-activated receptor-γ coactivator-1α-dependent vitamin D receptor pathway.
abstract: 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 D3were 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.
authors.affiliation: INSERM U954, Nutrition Génétique et Exposition aux Risques Environnementaux, Faculty of Medicine, University of Lorraine, Vandœuvre les Nancy, France; Division of Endocrinology, Regional University Hospital Center of Nancy, Vandœuvre les Nancy, France eva.feigerlova@chu-poitiers.fr.
authors.forename: Eva
authors.initials: E
authors.lastname: Feigerlova
authors.affiliation: INSERM U954, Nutrition Génétique et Exposition aux Risques Environnementaux, Faculty of Medicine, University of Lorraine, Vandœuvre les Nancy, France.
authors.forename: Lea
authors.initials: L
authors.lastname: Demarquet
authors.affiliation: INSERM U954, Nutrition Génétique et Exposition aux Risques Environnementaux, Faculty of Medicine, University of Lorraine, Vandœuvre les Nancy, France.
authors.forename: Hassan
authors.initials: H
authors.lastname: Melhem
authors.affiliation: INSERM U954, Nutrition Génétique et Exposition aux Risques Environnementaux, Faculty of Medicine, University of Lorraine, Vandœuvre les Nancy, France.
authors.forename: Rose
authors.initials: R
authors.lastname: Ghemrawi
authors.affiliation: INSERM U954, Nutrition Génétique et Exposition aux Risques Environnementaux, Faculty of Medicine, University of Lorraine, Vandœuvre les Nancy, France.
authors.forename: Shyue-Fang
authors.initials: SF
authors.lastname: Battaglia-Hsu
authors.affiliation: INSERM U954, Nutrition Génétique et Exposition aux Risques Environnementaux, Faculty of Medicine, University of Lorraine, Vandœuvre les Nancy, France.
authors.forename: Essi
authors.initials: E
authors.lastname: Ewu
authors.affiliation: INSERM U954, Nutrition Génétique et Exposition aux Risques Environnementaux, Faculty of Medicine, University of Lorraine, Vandœuvre les Nancy, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Alberto
authors.affiliation: INSERM U954, Nutrition Génétique et Exposition aux Risques Environnementaux, Faculty of Medicine, University of Lorraine, Vandœuvre les Nancy, France.
authors.forename: Deborah
authors.initials: D
authors.lastname: Helle
authors.affiliation: Division of Endocrinology, Regional University Hospital Center of Nancy, Vandœuvre les Nancy, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Weryha
authors.affiliation: INSERM U954, Nutrition Génétique et Exposition aux Risques Environnementaux, Faculty of Medicine, University of Lorraine, Vandœuvre les Nancy, France; jean-louis.gueant@medecine.uhp-nancy.fr.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
mesh_terms: D000818:Animals; D001846:Bone Development / Q000502:physiology*; D002117:Calcitriol / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047495:PPAR gamma / Q000378:metabolism*; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D002117:Calcitriol; D006360:Heat-Shock Proteins; D047495:PPAR gamma; D018167:Receptors, Calcitriol; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C579457:VDR protein, human
keywords: 1,25-dihydroxyvitamin D3; bone development; folate; osteoblast differentiation; vitamin B12