Abstract 4141690: Bisphosphonate therapy improves bone deficits but worsens arterial calcification in <i>Mgp</i> -null mice
Bibliographic record
Abstract
Background: Arterial calcification often occurs with bone mineral loss in osteoporosis, for which bisphosphonates are a standard therapy. Mice lacking the matrix GLA protein (Mgp) exhibit lethal arterial calcification and cranial bone formation deficits causing dental malocclusion. Mgp not only binds to hydroxyapatite but also inhibits the bone morphogenic protein activation of Runx2 transcription factor, which drives the osteogenic conversion of arterial smooth muscle cells (SMCs). Prior studies showed bisphosphate therapy ameliorates warfarin-induced arterial calcification in rats. This study investigated whether bisphosphonate (Alendronate,ALN) treatment could address bone deficits and arterial calcification in Mgp-null mice. Methods: Mgp-null mice were subjected to various doses of Alendronate therapy starting at weaning or postnatal day 3. Dental malocclusion severity was assessed by incisor trimming frequency. Arterial calcification was quantified by Alizarin red staining and µ-CT. Results: In Mgp-null mice, susceptibility to aortic artery calcification was not uniform but varied by location, with calcification highest at the proximal aorta. Of note, recurring nodes of calcification were found to correspond to branch points of vertebral arteries, with internodal regions showing less calcification. Alendronate therapy started at 3 weeks of age ameliorated dental malocclusion in Mgp-null mice of both sexes and improved but did not normalize body weight gain in males and females. However, no improvement in arterial calcification was observed at 7 weeks. Similarly, Alendronate therapy at lower doses from postnatal day 3 for 5 weeks ameliorated dental malocclusion and improved but did not normalize body weight gain in both sexes, while at higher doses, Alendronate prevented incisor development and caused growth retardation in both wild type and Mgp-null mice. However, Alendronate accelerated the appearance of Runx2 in SMCs of the aorta and worsened internodal arterial calcification in Mgp-null mice in a dose-dependent fashion, but not in Mgp-hemizygous or wild type mice. Conclusion: Our study reveals an important dichotomy in Mgp's function in bone and arteries. The bone deficits in Mgp-null mice, highlighted by incisor malocclusion, could be rescued by bisphosphonate treatment, whereas the arterial calcification could not. Thus, Mgp performs an essential function to prevent arterial calcification that cannot be restored by bisphosphonate therapy.
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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) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.007 | 0.003 |
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".