The Impact of Hypercholesterolemia on Tendon Injury Repair
Bibliographic record
Abstract
Background Hypercholesterolemia is a condition characterized by high blood cholesterol levels and is associated with tendon xanthomas (cholesterol deposits found on superficial tendons). Lipid accumulation in the tendon's extracellular spaces 1 may disrupt the parallel organization of collagen substructures within the tendon, and negatively affect its mechano‐sensing and mechanical properties, which may lead to injury. We hypothesized that tendon strength and metabolism would be inferior in a high cholesterol environment and attenuate the tendon's ability to repair after injury. Methods 50 Sprague‐Dawley (SD, control) and 50 apolipoprotein E knock‐out rats (ApoE, Envigo, IL, USA) rats bred in‐house were subject to a unilateral patellar tendon (PT) injury at 12 weeks of age; the uninjured limb served as a control. Animals were euthanased at 3, 14 or 42 days post‐injury, time‐points chosen to represent tendon inflammatory, reparative and remodelling repair phases, respectively. Animals were randomly assigned for investigating gene expression (SD/ApoE per timepoint n=4/4), tissue histology (n=6/6), biomechanical testing (n=10/10; 14 and 42 days only). Equal male/female ratios were used where possible (total SD M23/F27, ApoE M23/F26). Results ApoE total cholesterol was over double that of SD rats (mean 2.12 vs 0.99 mg/ml, p<0.001). Despite this, there was little histological evidence of lipid content (Oil Red‐O staining) in tendons of either group, and no apparent differences in tendon mechanical or material properties (Fig. 1). However, there were differences in gene expression (Fig. 2). ApoE rats demonstrated significantly greater COX2 expression than SD; other inflammatory markers (TGFβ, IL‐1, IL‐6) did not differ between groups. COL1A1, SCX, LOXα were significantly upregulated 14 days post injury in SD compared to ApoE. A greater COL3A1 response was also observed in ApoE compared to SD rats. Discussion We found differences in injury repair at the cellular level, using an ApoE high cholesterol model. There was little evidence of lipid accumulation at the tissue level, therefore the PT may have been a poor choice for an injury study in this instance and it is not surprising that biomechanical differences were not found. Moreover, ApoE rats were recently found to demonstrate only modest early atherosclerotic characteristics 2 , thus the young age of our cohort may be a primary factor in the lack of physical evidence of lipid accumulation. Nonetheless, our results indicate that even with a mild phenotype, high cholesterol significantly modulates tendon inflammatory and healing cellular activity, as indicated by altered mRNA levels, which may contribute to the known consequences of tendon cholesterol on tendons in humans. References 1 Grewal et al. 2014. Accumulation of oxidized LDL in the tendon tissues of C57BL/6 or apolipoprotein E knock‐out mice that consume a high fat diet: potential impact on tendon health. PLoS One 9(12): e114214. 2 Rune et al., 2018. Long‐term Western diet fed apolipoprotein E‐deficient rats exhibit only modest early atherosclerotic characteristics. Sci Rep 8(1): 5416.
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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) | 0.001 | 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".