High glucose alters tendon homeostasis through downregulation of the AMPK/Egr1 pathway

Abstract

Diabetes mellitus (DM) is associated with higher risk of tendinopathy, which reduces tolerance to exercise and functional activities and affects lifestyle and glycemic control. Expression of tendon-related genes and matrix metabolism in tenocytes are essential for maintaining physiological functions of tendon. However, the molecular mechanisms involved in diabetic tendinopathy remain unclear. We hypothesized that high glucose (HG) alters the characteristics of tenocyte. Using in vitro 2-week culture of tenocytes, we found that expression of tendon-related genes, including Egr1, Mkx, TGF-β1, Col1a2, and Bgn, was significantly decreased in HG culture and that higher glucose consumption occurred. Down-regulation of Egr1 by siRNA decreased Scx, Mkx, TGF-β1, Col1a1, Col1a2, and Bgn expression. Blocking AMPK activation with Compound C reduced the expression of Egr1, Scx, TGF-β1, Col1a1, Col1a2, and Bgn in the low glucose condition. In addition, histological examination of tendons from diabetic mice displayed larger interfibrillar space and uneven glycoprotein deposition. Thus, we concluded that high glucose alters tendon homeostasis through downregulation of the AMPK/Egr1 pathway and the expression of downstream tendon-related genes in tenocytes. The findings render a molecular basis of the mechanism of diabetic tendinopathy and may help develop preventive and therapeutic strategies for the pathology.

Metabolic shift from glycogen to trehalose promotes lifespan and healthspan in Caenorhabditis elegans

“…The changing human diet, in particular the large amount of added dietary sugar, has contributed to the increase in diabetes, obesity, and cardiovascular disease (1)(2)(3). Recent studies in mice found that a high-glucose diet significantly impaired healing following a tendon injury (65,66), demonstrating that high-sugar diets have far-reaching effects. Similar to previous studies (5)(6)(7)(8)(10)(11)(12)(13) and data in Fig.…”

Effects of Type II Diabetes Mellitus on Tendon Homeostasis and Healing

“…In similar studies, Ueda et al and Tsai et al found that culturing rat AT cells in high glucose (33 and 25 mM, respectively) for up to 72 h elicited increased expression of catabolic enzymes (matrix metalloproteinases [ Mmp ] 2, 9, and 13) and the pro‐inflammatory cytokine interleukin‐6 . In contrast to these acute exposures studies, Wu et al reported that culturing rat AT cells in high (25 mM) glucose‐containing medium for 2 weeks did not alter the expression of Scx , Tnmd , or Col1 , but did decrease the expression of other tendon‐related genes including mohawk, biglycan, and transforming growth factor β‐1. Collectively, these studies suggest that hyperglycemia may impair tendon cell homeostasis and alter the expression of pro‐inflammatory/pro‐fibrotic mediators.…”

EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

“…High glucose also affects tendon gene expression and cell behavior in tendon cell cultures, which induces changes in extracellular matrix [139]. Interestingly, Egr1 expression was also modified (associated with Mkx, Tgfb1, Col1a2, and Bgn expression alteration) in rat tendon cells cultured in high glucose for 14 days [46].…”

“…Glucose stimulation induces a rise in cytoplasmic Ca 2+ which is necessary for AP1, CRE, and SRE-mediated activation of Egr1 expression [45]. A high insulin and glucose concentration represses the phosphorylation of AMP-activated protein kinase (AMPK) in rat tenocytes, which prevents its positive role in Egr1 expression and alters tendon homeostasis [46].…”