The Polycomb Protein Bmi1 Plays a Crucial Role in the Prevention of 1,25(OH)2D Deficiency-Induced Bone Loss
Bibliographic record
Abstract
ABSTRACT We analyzed the skeletal phenotypes of heterozygous null Cyp27b1 (Cyp27b1+/−) mice and their wild-type (WT) littermates to determine whether haploinsufficiency of Cyp27b1 accelerated bone loss, and to examine potential mechanisms of such loss. We found that serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels were significantly decreased in aging Cyp27b1+/− mice, which displayed an osteoporotic phenotype. This was accompanied by a reduction of expression of the B lymphoma Moloney murine leukemia virus (Mo-MLV) insertion region 1 (Bmi1) at both gene and protein levels. Using chromatin immunoprecipitation (ChIP)-PCR, electrophoretic mobility shift assay (EMSA) and a luciferase reporter assay, we then showed that 1,25(OH)2D3 upregulated Bmi1 expression at a transcriptional level via the vitamin D receptor (VDR). To determine whether Bmi1 overexpression in mesenchymal stem cells (MSCs) could correct bone loss induced by 1,25(OH)2D deficiency, we overexpressed Bmi1 in MSCs using Prx1-driven Bmi1 transgenic mice (Bmi1Tg) mice. We then compared the bone phenotypes of Bmi1Tg mice on a Cyp27b1+/− background, with those of Cyp27b1+/− mice and with those of WT mice, all at 8 months of age. We found that overexpression of Bmi1 in MSCs corrected the bone phenotype of Cyp27b1+/− mice by increasing osteoblastic bone formation, reducing osteoclastic bone resorption, increasing bone volume, and increasing bone mineral density. Bmi1 overexpression in MSCs also corrected 1,25(OH)2D deficiency-induced oxidative stress and DNA damage, and cellular senescence of Cyp27b1+/− mice by reducing levels of reactive oxygen species (ROS), elevating serum total superoxide dismutase levels, reducing the percentage of γH2A.X, p16, IL-1β, and TNF-α–positive cells and decreasing γH2A.X, p16, p19, p53, p21, IL-1β, and IL-6 expression levels. Furthermore, 1,25(OH)2D stimulated the osteogenic differentiation of MSCs, both ex vivo and in vitro, from WT mice but not from Bmi1−/− mice and 1,25(OH)2D administration in vivo increased osteoblastic bone formation in WT, but not in Bmi1 −/− mice. Our results indicate that Bmi1, a key downstream target of 1,25(OH)2D, plays a crucial role in preventing bone loss induced by 1,25(OH)2D deficiency. © 2019 American Society for Bone and Mineral Research.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| 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) | 0.002 | 0.000 |
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".