Understanding cellular and molecular mechanisms of pathogenesis of diabetic tendinopathy

Figure 1 Mechanisms involved in the tenocytes during the process of diabetic tendinopathy. High glucose and high insulin inhibit the expression of the tendon-related genes TGF-β, collagen I, and biglycan in tenocytes by inactivating the AMPK/Egr1 pathway. In addition, high glucose promotes the adipogenic transdifferentiation of tenocytes and increases the protein expression of p-Akt and p-ERK1/2. Activation of the PI3K/Akt pathway plays an essential role in maintaining the expression of the adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and C/EBP, however, activation of ERK signaling downregulates PPARγ expression, suggesting the fibroblast-to-adipocyte phenotypic transition induced by high glucose which can be inhibited by Akt inhibitor LY294002 and promoted by ERK inhibitor PD98059. High glucose stimulates transglutaminase (Tgase) activity, leading to an increase in extracellular matrix degradation. Reactive oxygen species (ROS) accumulation is also increased in tenocytes under high glucose conditions, triggering the oxidative stress and increasing Tgase activity. Oxidative stress increases both FOXO1 and hypoxia-inducible factor-1α (HIF1α) expression in tenocytes. Under high glucose conditions, miR28-5p is also upregulated, especially in oxidative stress-treated tenocytes. miR28-5p directly inhibits the expression of the p53 deacetylase sirtuin 3, resulting in an increase in acetylated p53. p53 inhibits the expression of miR17-92, repressing the degradation of the proapoptotic protein Bim. Meanwhile, FOXO1 promotes the transcription of Bim, the gene product of which is a proapoptotic protein. Inhibition of Bim degradation and upregulation of Bim transcription synergistically result in an increase in Bim, facilitating the tenocyte apoptosis. However, under low glucose conditions, miR28-5p-sirt3-p53 pathway is not stimulated. Instead, p38 MAPK is activated and acts on both FOXO1 and HIF1α, resulting in the inhibition of FOXO1 transcriptional activity and activation of HIF1α. HIF1α enhances the expression of the tendon-related genes Sox9 and Scx. Advanced glycation end-products (AGEs), which bind to receptor for AGEs, impair the mitochondrial functions, affecting the DNA and mRNA synthesis in tenocytes. In addition, mitochondrial and total ROS/superoxide production are also remarkably increased in AGEs-treated tenocytes. AGEs: Advanced glycation end-products; RAGE: Receptor for AGEs; ROS: Reactive oxygen species; Tgase: Transglutaminase; Col I: Collagen I; Bgn: Biglycan; PPARγ: Peroxisome proliferator-activated receptor γ; HIF1α: Hypoxia-inducible factor-1α.