Ostm1 Bifunctional Roles in Osteoclast Maturation: Insights From a Mouse Model Mimicking a Human OSTM1 Mutation
Bibliographic record
Abstract
Ostm1 mutations are responsible for the most severe form of osteopetrosis in human and mice. To gain insight into Ostm1 cellular functions, we engineered a conditional in-frame deletion of the Ostm1 transmembrane domain and generated the first Ostm1 mouse model with a human mutation. Systemic targeting of Ostm1 loss of transmembrane domain produced osteopetrosis, as in the null Ostm1 gl/gl mouse. Significantly, conditional osteoclast targeting of Ostm1 resulted in similar osteopetrosis, thereby demonstrating that the intrinsic Ostm1 osteoclast deficiency is solely responsible for the mouse phenotype. Our analysis showed oversized osteoclasts with enhanced multinucleation associated with stimulation of intracellular calcium levels, of Nfatc1 nuclear re-localization, and of specific downstream Nfatc1 target genes, providing compelling evidence that Ostm1 is a negative regulator of preosteoclast fusion. Moreover, mature OCs with Ostm1 loss of transmembrane domain show appropriate levels of intracellular acidification but an altered distribution pattern, highlighting misregulation of endolysosome localization and dispersion. Consistently, the hydrolases tartrate-resistant acid phosphatase (TRAP) and cathepsin K (Ctsk) normally produced are sequestered within the osteoclasts and are not extracellularly secreted. These studies defined bifunctional roles for Ostm1 as a major regulator of preosteoclast cytoskeletal rearrangements toward cell multinucleation and of mature osteoclast intracellular lysosomal trafficking and exocytosis mechanism, both of which are essential for bone resorption. Importantly, these Ostm1 molecular and regulatory functions could serve as preclinical targets in this mouse model toward osteoclastogenic pathologies as osteoporosis and inflammation-induced bone loss. © 2018 American Society for Bone and Mineral Research.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 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".