1,25‐Dihydroxyvitamin D protects against age‐related osteoporosis by a novel VDR‐Ezh2‐p16 signal axis

Abstract

To determine whether 1,25-dihydroxyvitamin D (1,25(OH) 2 D) can exert an anti-osteoporosis role through anti-aging mechanisms, we analyzed the bone phenotype of mice with 1,25(OH) 2 D deficiency due to deletion of the enzyme, 25-hydroxyvitamin D 1α-hydroxylase, while on a rescue diet. 1,25(OH) 2 D deficiency accelerated age-related bone loss by activating the p16/p19 senescence signaling pathway, inhibiting osteoblastic bone formation, and stimulating osteoclastic bone resorption, osteocyte senescence, and senescence-associated secretory phenotype (SASP).Supplementation of exogenous 1,25(OH) 2 D 3 corrected the osteoporotic phenotype caused by 1,25(OH) 2 D deficiency or natural aging by inhibiting the p16/p19 pathway.The proliferation, osteogenic differentiation, and ectopic bone formation of bone marrow mesenchymal stem cells derived from mice with genetically induced deficiency of the vitamin D receptor (VDR) were significantly reduced by mechanisms including increased oxidative stress, DNA damage, and cellular senescence. We also demonstrated that p16 deletion largely rescued the osteoporotic phenotype caused by 1,25(OH) 2 D 3 deficiency, whereas 1,25(OH) 2 D 3 could up-regulate the enzyme Ezh2 via VDR-mediated transcription thereby enriching H3K27me3 and repressing p16/p19 transcription. Finally, we demonstrated that treatment with 1,25(OH) 2 D 3 improved the osteogenic defects of human BM-MSCs caused by repeated passages by stimulating their proliferation and inhibiting their senescence via the VDR-Ezh2-p16 axis. The results of this study therefore indicate that 1,25(OH) 2 D 3 plays a role in preventing age-related osteoporosis by up-regulating Ezh2 via VDR-mediated transcription, increasing H3K27me3 and repressing p16 transcription, thus promoting the proliferation and osteogenesis of BM-MSCs and inhibiting their senescence, while also stimulating osteoblastic bone formation, and inhibiting osteocyte senescence, SASP, and osteoclastic bone resorption. K E Y W O R D Scellular senescence, Ezh2, osteogenesis, osteoporosis, p16, Vitamin D

FOXC1-mediated LINC00301 facilitates tumor progression and triggers an immune-suppressing microenvironment in non-small cell lung cancer by regulating the HIF1α pathway

“…Herein, A549 and SPC-A-1 cells were transfected with sh-NC and sh-LINC00301, respectively. Then, qPCR was conducted to examine the mRNA levels of EZH2 target suppressive genes [20,22,33,[36][37][38][39][40], including p15, p16, p21, p57, KLF2, PTEN, LATS2, RRAD, ASPP2, E-cadherin, and EAF2. The results demonstrated that the silence of LINC00301 remarkably increased the EAF2 mRNA level in both A549 and SPC-A-1 cells (Fig.…”

SIRT1/FOXO3a axis plays an important role in the prevention of mandibular bone loss induced by 1,25(OH)2D deficiency

“…Our previous studies, using homozygous knockout of 1α(OH)ase (Cyp27b1) (in 1α(OH)ase -/- mice) or double homozygous knockout of 1α(OH)ase and the parathyroid hormone gene ( Pth ) or double homozygous knockout of 1α(OH)ase and the calcium sensitive receptor gene ( Casr ), demonstrated that endogenous and exogenous 1,25(OH) 2 D could directly stimulate osteoblastic bone formation via the VDR 6 - 10 . Recently we further demonstrated that 1,25(OH) 2 D plays an anti-osteoporotic role via transcriptionally up-regulating expression of Bmi1 and Ezh2 in osseous cells via the VDR, subsequently, inhibiting oxidative stress and DNA damage, inactivating the p16 and p19 signaling pathways, inducing osseous cell senescence and SASP, facilitating osteoblastic bone formation, and inhibiting osteoclastic bone resorption 11 , 12 . These studies focused on long bone or vertebrae, however, the role and mechanism of 1,25(OH) 2 D in preventing mandibular bone loss 13 is less well investigated.…”

The latitude hypothesis, vitamin D, and SARS-Co-V2

“…Interest in vitamin D research is reflected in nine articles in April and May of 2020 retrieved on PubMed (Sayers et al., 2020 ). Particularly, in those studies it was shown that 25(OH)D levels are lower in patients with positive PCR for SARS-CoV-2 (D’Avolio et al., 2020 ), that 1,25(OH) 2 D can protects against age-related osteoporosis (Yang et al., 2020 ), and that the hypovitaminosis D contributes to the sex-specific SARS-CoV-2 mortality (La Vignera et al., 2020 ). It was also pointed out that the levels of vitamin D might impact mortality from the SARS-CoV-2 infection (Marik et al., 2020 ), and that therefore vitamin D might play a role in the prevention of COVID-19 infection and mortality (Carter et al., 2020 ; Ilie et al., 2020 ; Jakovac, 2020 ).…”