Feigerlova Eva, Demarquet Lea, Melhem Hassan, Ghemrawi Rose, Battaglia-Hsu Shyue-Fang, Ewu Essi, Alberto Jean-Marc, Helle Deborah, Weryha Georges, Guéant Jean-Louis
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
INSERM U954, Nutrition Génétique et Exposition aux Risques Environnementaux, Faculty of Medicine, University of Lorraine, Vandœuvre les Nancy, France.
FASEB J. 2016 Oct;30(10):3598-3612. doi: 10.1096/fj.201600332R. Epub 2016 Jul 19.
Deficiency in methyl donor (folate and vitamin B) 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 D 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.
甲基供体（叶酸和维生素B）以及维生素D缺乏与骨骼发育异常独立相关。此前研究表明，甲基供体缺乏（MDD）会削弱大鼠幼崽体内核受体共激活因子过氧化物酶体增殖物激活受体γ共激活因子1α（PGC1α）的活性，影响包括雌激素受体α和雌激素相关受体α在内的核信号传导；然而，其对维生素D受体（VDR）信号传导的影响尚不清楚。我们研究了大鼠幼崽在MDD状态下的骨骼发育情况，并利用人MG-63前成骨细胞来更好地理解相关分子机制。在幼鼠中，MDD降低了全身骨矿物质密度，缩短了胫骨长度，并损害了生长板成熟；在前成骨细胞中，MDD减缓了细胞增殖。机制研究表明，在大鼠股骨近端骨干和MG-63细胞中，VDR、雌激素受体α、PGC1α、精氨酸甲基转移酶1和沉默调节蛋白1的表达均降低，同时MG-63细胞中核VDR与PGC1α的相互作用也减少。VDR与PGC1α之间较弱的相互作用可能归因于蛋白表达降低、PGC1α甲基化/乙酰化失衡以及热休克蛋白90（HSP90）对核VDR的隔离。这些因素共同损害了骨骼发育，表现为骨碱性磷酸酶降低以及促脂肪生成的过氧化物酶体增殖物激活受体γ、脂联素和雌激素相关受体α表达增加。有趣的是，在MDD状态下，1,25-二羟基维生素D对骨骼发育的作用无效，而添加S-腺苷甲硫氨酸可以挽救这种情况，它能恢复精氨酸甲基转移酶1、PGC1α、脂联素和HSP90的表达。总之，MDD通过破坏VDR与PGC1α的相互作用以及由于HSP90过表达导致的核VDR隔离，使维生素D信号失活。这些数据表明，在MDD状态下维生素D治疗可能无效。——费格洛娃，E.，德马尔凯，L.，梅尔赫姆，H.，盖姆拉维，R.，巴塔利亚-许，S.-F.，埃武，E.，阿尔贝托，J.-M.，埃勒，D.，韦里哈，G.，盖昂，J.-L. 甲基供体缺乏通过过氧化物酶体增殖物激活受体γ共激活因子1α依赖的维生素D受体途径损害骨骼发育
