Hyperglycemia augments the adipogenic transdifferentiation potential of tenocytes and is alleviated by cyclic mechanical stretch
Journal
International Journal of Molecular Sciences
Journal Volume
19
Journal Issue
1
Pages
90
Date Issued
2018
Author(s)
Abstract
Diabetes mellitus is associated with damage to tendons, which may result from cellular dysfunction in response to a hyperglycemic environment. Tenocytes express diminished levels of tendon-associated genes under hyperglycemic conditions. In contrast, mechanical stretch enhances tenogenic differentiation. However, whether hyperglycemia increases the non-tenogenic differentiation potential of tenocytes and whether this can be mitigated by mechanical stretch remains elusive. We explored the in vitro effects of high glucose and mechanical stretch on rat primary tenocytes. Specifically, non-tenogenic gene expression, adipogenic potential, cell migration rate, filamentous actin expression, and the activation of signaling pathways were analyzed in tenocytes treated with high glucose, followed by the presence or absence of mechanical stretch. We analyzed tenocyte phenotype in vivo by immunohistochemistry using an STZ (streptozotocin)-induced long-term diabetic mouse model. High glucose-treated tenocytes expressed higher levels of the adipogenic transcription factors PPARγ and C/EBPs. PPARγ was also highly expressed in diabetic tendons. In addition, increased adipogenic differentiation and decreased cell migration induced by high glucose implicated a fibroblast-to-adipocyte phenotypic change. By applying mechanical stretch to tenocytes in high-glucose conditions, adipogenic differentiation was repressed, while cell motility was enhanced, and fibroblastic morphology and gene expression profiles were strengthened. In part, these effects resulted from a stretch-induced activation of ERK (extracellular signal-regulated kinases) and a concomitant inactivation of Akt. Our results show that mechanical stretch alleviates the augmented adipogenic transdifferentiation potential of high glucose-treated tenocytes and helps maintain their fibroblastic characteristics. The alterations induced by high glucose highlight possible pathological mechanisms for diabetic tendinopathy. Furthermore, the beneficial effects of mechanical stretch on tenocytes suggest that an appropriate physical load possesses therapeutic potential for diabetic tendinopathy. ? 2017 by the authors. Licensee MDPI, Basel, Switzerland.
SDGs
Other Subjects
cadherin; mitogen activated protein kinase; peroxisome proliferator activated receptor gamma; protein kinase B; streptozocin; transcription factor RUNX2; transcription factor Sox9; transforming growth factor; CCAAT enhancer binding protein beta; Cebpb protein, rat; glucose; mitogen activated protein kinase 1; mitogen activated protein kinase 3; peroxisome proliferator activated receptor gamma; protein kinase B; streptozocin; animal model; animal tissue; antibody labeling; Article; cell isolation; cell migration; cell migration assay; cell motility; cell transdifferentiation; diabetes mellitus; enzyme induction; gene expression; gene sequence; glucose blood level; hyperglycemia; immunofluorescence; immunohistochemistry; mouse; nonhuman; protein expression; reverse transcription polymerase chain reaction; RNA extraction; streptozotocin-induced diabetes mellitus; tenocyte; Western blotting; wound healing; adipocyte; adipogenesis; animal; biomechanics; cell transdifferentiation; chemically induced; drug effect; experimental diabetes mellitus; gene expression regulation; genetics; male; mechanical stress; mechanotransduction; metabolism; pathology; primary cell culture; rat; Sprague Dawley rat; tendon; tenocyte; Adipocytes; Adipogenesis; Animals; Biomechanical Phenomena; CCAAT-Enhancer-Binding Protein-beta; Cell Transdifferentiation; Diabetes Mellitus, Experimental; Gene Expression Regulation; Glucose; Male; Mechanotransduction, Cellular; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; PPAR gamma; Primary Cell Culture; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Streptozocin; Stress, Mechanical; Tendons; Tenocytes
Type
journal article