Hypoxia-induced Abrogation of Contact-dependent Inhibition of Rheumatoid Arthritis Synovial Fibroblast Proliferation
Bibliographic record
Abstract
OBJECTIVE: Uncontrolled proliferation of synovial fibroblasts is characteristic of the pathology of rheumatoid arthritis (RA). Since synovial tissues in the rheumatoid joints are hypoxic, we investigated how hypoxia affects RA synovial fibroblast (RASF) proliferation. METHODS: RASF were cultured at 2000 cells (low density culture) or at 5000 cells (high density, growth-inhibitory confluent culture) per microtiter well under hypoxic (10%, 3%, or 1% O2) or normoxic (21% O2) conditions. Some RASF were treated with recombinant human interleukin 1 receptor antagonist (IL-1ra), anti-tumor necrosis factor-alpha (TNF-alpha)-neutralizing antibodies, anti-N-cadherin-blocking antibodies, or MG132. 3H-labeled thymidine incorporation was quantified to assess their proliferation. Total RNA and cell lysates were prepared for real-time polymerase chain reaction and Western blot analyses. RESULTS: Hypoxia exerted no effect on proliferation of RASF cultured at low density. At high density, it abrogated contact-dependent growth inhibition of RASF, but not of human dermal fibroblasts. Addition of anti-TNF-alpha antibodies or IL-1ra did not affect the results. Upregulated expression of cyclin-dependent kinase inhibitor p27Kip1 was observed in the cells cultured at high density under normoxic conditions, but not under hypoxic conditions. Hypoxia decreased N-cadherin expression on RASF. Addition of anti-N-cadherin-blocking antibodies mimicked the effects of hypoxic culture; it promoted proliferation of RASF cultured at high density under normoxic conditions. This antibody treatment also downmodulated p27Kip1 expression. CONCLUSION: Hypoxia downregulates N-cadherin expression on RASF, and thus prevents p27Kip1 upregulation for their contact inhibition. It is likely that hypoxia in rheumatoid synovial tissues contributes to rheumatoid pathology by augmenting proliferation of synovial fibroblasts.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".