Methyl donor deficiency impairs bone developmentviaperoxisome proliferator‐activated receptor‐γ coactivator‐1α–dependent vitamin D receptor pathway

Abstract

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.

Supplementation of Methyl-Donor Nutrients to a High-Fat, High-Sucrose Diet during Pregnancy and Lactation Normalizes Circulating 25-Dihydroxycholecalciferol Levels and Alleviates Inflammation in Offspring

“…Furthermore, cathelicidin has been shown to activate TLR4 signaling and modulate inflammatory status in vivo [47]. Though it is still unclear how MS mediated the restorative effect of VD status among offspring, folate and vitamin B 12 deficiencies have been shown to suppress VDR protein levels in bone cells in vitro [28]. This may indicate a critical role of MS nutrients in mediating VD signaling and subsequent inflammatory responses among the offspring.…”

“…A recent European prospective cohort study reported a diet rich in methyl-donor nutrients, such as folate, vitamin B 12 , choline, methionine, and betaine, was associated with global methylation changes [26], which were linked to risks of cardiometabolic diseases among offspring [27]. Previously, an in vivo rat study showed that maternal methyldonor nutrient deficiency downregulated the gene expression of VDR and reduced the bioavailability of active VD [28]. However, the role of methyl-donor nutrients in modulating methylation status of VD-related genes under obesogenic environment remain unclear.…”

Interplay of Vitamin D and SIRT1 in Tissue-Specific Metabolism—Potential Roles in Prevention and Treatment of Non-Communicable Diseases Including Cancer

“…Evidence shows a direct and indirect connection of vitamin D and SIRT1, where direct influence exists, on the one hand, through binding of VDR to SIRT1 promoter or to SIRT1 and other proteins in a transcription complex [ 3 , 7 , 13 , 207 , 209 , 216 , 217 , 218 ] and, on the other hand, through epigenetic modifications, by regulating each other [ 13 , 32 , 219 ]. The indirect routes involve activation of signaling pathways by molecules such as adiponectin, AMPK, resveratrol, methyl-donors, etc., which upregulate/activate either SIRT1 or vitamin D pathways [ 8 , 49 , 96 , 220 , 221 , 222 , 223 , 224 ]. We briefly summarize the possible interaction of vitamin D and SIRT1 in relation to the regulation of signaling pathways and targeted molecules in Figure 2 .…”

Sirt1-PPARS Cross-Talk in Complex Metabolic Diseases and Inherited Disorders of the One Carbon Metabolism

“…In young rats, MDD decreases the total body bone mineral density, reduced tibia length and impaired growth plate maturation, and in preosteoblasts, MDD slows cellular proliferation. MDD produces a decreased expression of VDR, estrogen receptor-α, PGC1α, PRMT1 and Sirt1 and decreased nuclear VDR-PGC1α interaction [ 99 ]. The weaker VDR-PGC1α interaction is attributed to the reduced expression and imbalanced methylation/acetylation of PGC1α and the nuclear VDR sequestration by heat shock protein 90 (HSP90).…”

“…The weaker VDR-PGC1α interaction is attributed to the reduced expression and imbalanced methylation/acetylation of PGC1α and the nuclear VDR sequestration by heat shock protein 90 (HSP90). These mechanisms together compromise bone development, as reflected by lowered bone alkaline phosphatase and increased proadipogenic PPARγ, adiponectin and estrogen-related receptor-α expression [ 99 ].…”