The alarmin S100A9 hampers osteoclast differentiation from human circulating precursors by reducing the expression of RANK
Bibliographic record
Abstract
ABSTRACT The alarmin S100A8/A9 is implicated in sterile inflammation‐induced bone resorption and has been shown to increase the bone‐resorptive capacity of mature osteoclasts. Here, we investigated the effects of S100A9 on osteoclast differentiation from human CD14 + circulating precursors. Hereto, human CD14 + monocytes were isolated and differentiated toward osteoclasts with M‐CSF and receptor activator of NF‐κB (RANK) ligand (RANKL) in the presence or absence of S100A9. Tartrate‐resistant acid phosphatase staining showed that exposure to S100A9 during monocyte‐to‐osteoclast differentiation strongly decreased the numbers of multinucleated osteoclasts. This was underlined by a decreased resorption of a hydroxyapatite‐like coating. The thus differentiated cells showed a high mRNA and protein production of proinflammatory factors after 16 h of exposure. In contrast, at d 4, the cells showed a decreased production of the osteoclast‐promoting protein TNF‐α. Interestingly, S100A9 exposure during the first 16 h of culture only was sufficient to reduce osteoclastogenesis. Using fluorescently labeled RANKL, we showed that, within this time frame, S100A9 inhibited the M‐CSF‐mediated induction of RANK. Chromatin immunoprecipitation showed that this was associated with changes in various histone marks at the epigenetic level. This S100A9‐induced reduction in RANK was in part recovered by blocking TNF‐α but not IL‐1. Together, our data show that S100A9 impedes monocyte‐to‐osteoclast differentiation, probably via a reduction in RANK expression.—Di Ceglie, I., Blom, A. B., Davar, R., Logie, C., Martens, J. H. A., Habibi, E., Böttcher, L.‐M., Roth, J., Vogl, T., Goodyear, C. S., van der Kraan, P. M., van Lent, P. L., van den Bosch, M. H. The alarmin S100A9 hampers osteoclast differentiation from human circulating precursors by reducing the expression of RANK. FASEB J. 33, 10104–10115 (2019). www.fasebj.org
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 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) | 0.000 | 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".