1,25‐Dihydroxyvitamin D protects against age‐related osteoporosis by a novel VDR‐Ezh2‐p16 signal axis
Why this work is in the frame
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Bibliographic record
Abstract
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.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it