Claudin‐2 or Claudin ‐12 Is Required to Maintain Calcium Homeostasis
Bibliographic record
Abstract
Calcium (Ca 2+ ) is a mineral vital for a myriad of physiological functions with homeostasis maintained by interactions between intestinal absorption, renal reabsorption and bone mineralization. Intestinal and renal (re)absorption occurs via transcellular and paracellular pathways with the paracellular pathway hypothesized to predominate in both tissues. Paracellular intestinal Ca 2+ absorption is thought to occur primarily in the distal small intestine with the colon contributing a negligible amount to overall homeostasis. Claudins are tight junction proteins that confer paracellular permeability properties to epithelia. Claudins‐2 and ‐12 mediate Ca 2+ permeability to intestinal and renal epithelial cell models. However, deletion of either claudin in a mouse model does not result in a negative Ca 2+ balance, suggesting the compensation of one by the other. We hypothesized, therefore, that claudin‐2 and claudin‐12 form independent cation permeable pores in intestinal and renal epithelium thereby enabling the maintenance of Ca 2+ homeostasis. To test this hypothesis, we generated claudin‐2 and claudin‐12 double knockout mice, which displayed a decreased Ca 2+ balance due to reduced intestinal absorption and further increased urinary excretion than single claudin‐2 knockout mice (N.B. claudin‐12 KO mice do not have hypercalciuria). These perturbations resulted in decreased serum ionized Ca 2+ and markedly decreased bone mineralization. Moreover, double knockout mice did not have the expected increase in serum 1,25(OH) 2 ‐vitamin D and expression of genes mediating transcellular Ca 2+ absorption, which are transcriptionally regulated by vitamin D. However, DKO mice increased serum Ca 2+ and urinary Ca 2+ excretion in response to calcitriol administration. Consistent with each claudin forming an independent Ca 2+ pore, claudin‐2 and claudin‐12 did not co‐immunoprecipitate in cell culture, and colonic Ca 2+ permeability of double knockout determined in Ussing chambers mice was further reduced than the individual knockouts. Surprisingly, small bowel Ca 2+ permeability was not different from wild‐type in any of the genotypes. Together this data is consistent with claudin‐2 and claudin‐12 independently mediating paracellular colonic Ca 2+ absorption and renal Ca 2+ reabsorption; processes critical to the maintenance of Ca 2+ homeostasis.
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How this classification was reachedexpand
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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".