title: 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.
authors.affiliation: School and Graduate Institute of Physical Therapy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Fu
authors.initials: YF
authors.lastname: Wu
authors.affiliation: School and Graduate Institute of Physical Therapy, College of Medicine, National Taiwan University, Taipei, Taiwan.|Center of Physical Therapy, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hsing-Kuo
authors.initials: HK
authors.lastname: Wang
authors.affiliation: Nephrology Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Chang
authors.affiliation: Sports and Health Research Center, Tongji University Department of Physical Education, Shanghai, China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Orthopedic Surgery, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Orthopedic Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Jui-Sheng
authors.initials: JS
authors.lastname: Sun
authors.affiliation: School and Graduate Institute of Physical Therapy, College of Medicine, National Taiwan University, Taipei, Taiwan.|Center of Physical Therapy, National Taiwan University Hospital, Taipei, Taiwan.|Rehabilitation Center, National Taiwan University Hospital Chu-Tung Branch, Hsinchu County, Taiwan.
authors.forename: Yuan-Hung
authors.initials: YH
authors.lastname: Chao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000125:Achilles Tendon / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects*; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D052256:Tendinopathy / Q000378:metabolism / Q000473:pathology; D000070916:Tenocytes / Q000378:metabolism* / Q000473:pathology
chemical_list: D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D055372:AMP-Activated Protein Kinases; D005947:Glucose