The role of inositol polyphosphate 4-phosphatase type II alpha (Inpp4bα) in mature osteoclasts «in vivo»
Bibliographic record
Abstract
Osteopetrosis is a genetic disorder resulting from excessive amount of bone due to a defect in osteoclasts. Our laboratory characterized the Ostm1 gene that is responsible for the most severe form of osteopetrosis in mice and humans. In addition, our laboratory then identified the Inositol polyphosphate 4- phosphatase type II alpha (Inpp4b alpha) gene in a differential display screen with reduced expression in Ostm1 deficient osteoclasts. Following characterization of the mouse Inpp4b gene, its role in bone biology was investigated. First, Inpp4b alpha co-localized with F-actin in the podosome subunits, which forms the actin ring of the osteoclast cytoskeletal structure that is essential for osteoclast resorption activity. Second, expression of the phosphatase-inactive Inpp4b in RAW 264.7 OCLs resulted in the formation of multiple, small actin rings leading to poor bone resorption. This result suggested that the phosphatase catalytic activity of Inpp4b alpha is crucial for osteoclast actin ring formation and cytoskeletal dynamics in vitro. We then hypothesized that Inpp4b alpha can be an essential phosphatase involved in the osteoclast cytoskeleton and resorption activity in vivo. Toward this aim, we decided to overexpress three forms of Inpp4b in transgenic mice: the native Inpp4b alpha, the Inpp4b alpha phosphatase inactive form (C845A), and the native form missing the lipid binding C2 domain. Specific expression of these transgenes was targeted with the human Ctsk promoter, which is specifically expressed in mature osteoclasts. These mice were also crossed with Inpp4b knockout mice to avoid interference with expression of endogenous Inpp4b and to mimic a knock-in situation. The expression of Inpp4b alpha (C845A) OCLs differentiated in ex vivo presented multiple, small actin rings and disruption in cytoskeletal rearrangement correlating with previous results. The expression of Inpp4b alpha missing the C2 domain had a diffused podosome belt, similar to osteoclasts derived from the Inpp4b knockout mice. These results illustrated that Inpp4b alpha plays a major role in the osteoclast cytoskeletal rearrangements in vivo, and this is directly dependent on the catalytic activity of the Inpp4b phosphatase.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".