Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production
Bibliographic record
Abstract
Cartilage degradation in osteoarthritis (OA) and rheumatoid arthritis constitutes a major structural change in the joint, which may severely impair its function causing pain and disability. This degradation is accompanied by the release in the synovial fluid of degraded matrix constituents that primarily result from an increased matrix catabolism. Various factors are directly involved in this process. Endothelin-1 (ET-1), a potent vasoconstrictor and promitogen peptide for many cell types, including chondrocytes, was recently identified as one such factor. We previously demonstrated that ET-1 induces matrix metalloproteinase (MMP)-1 and MMP-13 synthesis, secretion and activation. Here, we investigated the mechanism by which ET-1 induces the production of these two MMPs. Human OA chondrocytes were cultured in the presence of ET-1 with or without inhibitors of protein kinase or LY83583 (an inhibitor of soluble guanylate cyclase and of cGMP) and then MMP-1, MMP-13 and nitric oxide (NO) levels were measured by ELISA and Griess reaction, respectively. Additionally, inducible nitric oxide synthase (iNOS) and activated forms of p38 mitogen-activated protein kinase, p44/42, SAP/JNK and serine threonine kinase Akt were determined by western blot, Bad and Bcl2 proteins by immunocytochemistry and apoptosis by TUNEL. ET-1 greatly increased MMP-1 and MMP-13 production, NO release and iNOS expression. LY83583 decreased the production of both MMPs below basal levels, whereas the inhibitor of p38 kinase, SB202190, suppressed ET-1-stimulated production only. Similarly, the ET-1-induced NO production was partially suppressed by the p38 kinase inhibitor and completely suppressed by the PKA kinase inhibitor, KT5720, and LY83583, suggesting the involvement of these enzymes in ET-1 signaling pathways. ET-1 does not induce apoptosis and could even have a protective effect through the induction of Akt phosphorylation. In human OA chondrocytes, ET-1 controls the production of MMP-1 and MMP-13. ET-1 also induces NO release via iNOS induction. Thus, ET-1 and NO should become important target molecules for future therapies aimed at stopping cartilage destruction.
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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 | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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) | 0.000 | 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".