Abstract 192: Scleraxis is a Required Component of the Cardiac Extracellular Matrix Gene Expression Program
Bibliographic record
Abstract
The collagenous cardiac extracellular matrix (ECM) reinforces the myocardium and facilitates intercellular communication, but excessive ECM production in fibrosis results in dysfunction and heart failure. The transcription factor scleraxis directly governs expression of type I fibrillar collagen in ECM-rich tissues including tendons and the heart. We have also shown that scleraxis is required for collagen 1α2 gene expression induced by the potent pro-fibrotic TGFβ-Smad signaling pathway. We therefore examined the broader role of scleraxis in myocardial ECM production, including mechanisms regulating the expression of scleraxis itself. Scleraxis knockout in mice resulted in a dramatic ~50% loss of cardiac ECM components including fibrillar collagens, proteoglycans and matrix metalloproteinases, concomitant with a significant decrease in fibroblast number. Scleraxis knockdown in primary cardiac proto-myofibroblasts recapitulated these changes without increasing cell death, suggesting a reduction in fibroblast precursors in knockout mice in vivo. Conversely, over-expression of scleraxis had the opposite effect, up-regulating expression of ECM genes and numerous markers indicative of increased commitment to a myofibroblast cell fate. Scleraxis increased proto-myofibroblast contractility via direct transactivation of the α-smooth muscle actin promoter. Similar to TGFβ, pro-fibrotic angiotensin II and Connective Tissue Growth Factor induced scleraxis expression, suggesting that scleraxis behaves as a common transcriptional effector for multiple fibrotic pathways. Fibrillar collagen gene expression induced by these factors was significantly attenuated by scleraxis knockdown, further implicating scleraxis in fibrotic ECM synthesis. Intriguingly, the histone deacetylase inhibitor trichostatin A, which has been reported to exert anti-fibrotic effects in the heart, significantly reduced scleraxis expression in cardiac myofibroblasts. These data collectively identify scleraxis as a central and requisite transcriptional regulator of fibroblast phenotype and the ECM gene expression program in the heart, and provide rationale for the investigation of anti-scleraxis strategies to attenuate fibrosis in patients.
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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 | 0.000 |
| 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".