Modulation of EGR1 Expression by Hyperglycemia in Swine Rotator Cuff Tendons

Author(s): Joey Day, Resmi Rajalekshmi, Devendra K. Agrawal

Diabetes mellitus is known to impair tendon structure and function, yet the molecular mechanisms linking hyperglycemia to tendon degeneration remain poorly understood. This study investigated the expression of early growth response-1 (EGR1) and its association with toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) signaling pathways in the rotator cuff tendons of hyperglycemic swine, a model chosen for its anatomical similarity to humans. Rotator cuff tendon tissues were collected from normal and hyperglycemic swine and analyzed using histology, qRT-PCR, Western blotting, and immunohistochemistry. Histological evaluation revealed altered tenocyte morphology and increased cellularity in hyperglycemic tendons. qRT-PCR results showed significant transcriptional upregulation of EGR1, TLR4, and NF-κB in hyperglycemic samples, suggesting activation of inflammatory and stress-response pathways. However, protein analysis revealed a non-significant decrease in EGR1 levels and modest increases in TLR4 and NF-κB, indicating possible post-transcriptional regulation. This discrepancy between mRNA and protein levels of EGR1 may be attributed to altered stress granule dynamics under hyperglycemic conditions. These findings elucidate a novel interplay among metabolic stress, innate immune signaling, and translational regulation in tendon tissue, proposing that targeting TLR4 signaling or stress granule formation may offer therapeutic potential for preserving tendon integrity in diabetic patients.