SAT-392 The Role of β-arrestin2 in Bone Catabolic Response to Hyperparathyroidism In Vivo
Bibliographic record
Abstract
Abstract Primary hyperparathyroidism (PHPT) is an endocrine disorder characterized by elevated parathyroid hormone (PTH) levels and hypercalcemia caused by the overactive parathyroid glands, resulting in negative impacts on the skeleton including bone loss and increased bone fragility1. PTH binds and activates parathyroid hormone type 1 receptor (PTH1R) which primary couples to Gαs, stimulating the downstream effectors that mediate bone remodeling processes2. PTH1R activity is regulated by arrestins, specially β-arrestin2 (β-arr2), through signal termination and receptor internalization2. Previously, we have seen anabolic effects of hyperparathyroidism (cPTH) on trabecular bone in mice overexpressing Gαs3. We hypothesized that increased Gαs protein levels in osteoblasts outcompete β-arr binding to PTH1R, leading to reduced signal termination and increased bone formation. To test this hypothesis, we are testing if the deletion of β-arr2 will also result in an anabolic response to cPTH in this study. The response of β-arr2 knockout (KO) mice to cPTH have yet to be documented. The hypothesis of this study is that β-arr2 KO mice treated with cPTH will exhibit anabolic effects on the trabecular bone. Nine-week-old wild-type (WT) C57BL/6 and β-arr2 KO mice were treated for 14 days with either rPTH1-34 (80ng/g/day) or saline (PBS) using micro-osmotic pumps to simulate hyperparathyroidism. There are 8 groups (n=10 per group) including both sexes, 2 genotypes (WT and KO), and 2 treatment groups (PTH and PBS). Two 30 mg/kg doses of 0.6% calcein green were administered subcutaneously to mice at 7 and 2 days prior to euthanasia to label bones. Decalcified tibiae were embedded in paraffin for histological analysis. Undecalcified tibiae were embedded in plastic for dynamic histomorphometry. Micro-computed tomography (μCT) was used to access bone microarchitecture of femurs and vertebrae followed by biomechanical testing of bone strength. The μCT data of distal femurs show that cPTH treatment increased bone volume in female KO mice (6.864 ± 2.318 vs 4.690 ± 1.555 %; P= 0.0328; n=9 per group) and maintained bone in male KO mice (13.37 ± 2.860 vs 13.38 ± 3.135; P= 0.9968, n= 10) compared to control. Histological analysis show higher osteoclastic activity in both sexes and genotypes when treated with cPTH, suggesting that the anabolic response may be at the level of osteoblasts and osteocytes. These promising results support our hypothesis that arrestin-mediated PTH receptor downregulation plays an importance role in bone weakness associated with hyperparathyroidism. These studies are important for understanding the clinical phenotype of PHPT patients and suggest that inhibition of β-arr2 in PHPT could be a path for drug therapy. References: (1) Mosekilde L. Clin Endocrinol 2008;69:1-9. (2) Ferrari SL et al., J Biol Chem 1999; 274:29968–29975 (3) Zhang L. PhD thesis University of Toronto, 2018.
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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 | 0.000 | 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) | 0.004 | 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 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".