Scleraxis: A Novel Transcriptional Regulator of Cardiac Fibroblast Function and Phenotype
Bibliographic record
Abstract
The cardiac extracellular matrix (ECM) plays a crucial role in maintenance of mechanical integrity, initiation of biochemical signaling and facilitation of intercellular communication in the myocardium. Increased ECM production due to chronic stress impairs cardiac function leading to heart failure. Our laboratory has previously reported that the transcription factor scleraxis (Scx) directly regulates collagen 1α2 gene expression in primary cardiac fibroblasts, and is up‐regulated in response to TGF‐β signaling and in post‐infarct scar tissue. Here we examined the regulatory role of Scx in basal ECM synthesis in vivo. Scx null hearts exhibited a significant reduction in fibrillar collagens, proteoglycans and matrix metalloproteinases. Exogenous Scx gene delivery was sufficient to rescue these down‐regulated target genes in cardiac myofibroblasts derived from Scx null mice. Gain and loss‐of‐function studies in cardiac proto‐myofibroblasts resulted in a significant upregulation or downregulation of fibroblast phenoconversion markers. Scx caused a direct transactivation of the α‐smooth muscle actin (αSMA) gene promoter, increasing synthesis of αSMA + stress fibers and contractility. Interestingly, the ECM‐producing DDR2 + fibroblasts were significantly reduced in null hearts due to altered fibroblast development as demonstrated by decreased mesenchymal and increased epithelial marker gene expression. These findings collectively support Scx's novel role as a required regulator of cardiac fibroblast function and phenotype thus providing a rationale for development of anti‐fibrotic drugs targeting scleraxis.
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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 | 0.001 | 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".