A high glucose level stimulate inflammation and weaken pro-resolving response in tendon cells – A possible factor contributing to tendinopathy in diabetic patients

Abstract

BackgroundTendinopathy is a chronic disorder that affects a huge population, and is causing high socioeconomical impacts worldwide. Tendinopathy was reported to be more prevalent in diabetic patients, and chronic inflammation was proposed to play an important role in its development. It was also known that diabetic patients present in a pro-inflammatory state. There is a possibility that the high glucose environment in diabetic patients lead to chronic inflammation in the tendon, and eventually the development of tendinopathy. In this study, we would simulate the diabetic environment in an in vitro setup, to assess the effect of a high glucose level on cultured tendinopathic and healthy tendon derived stem cells (TDSCs) under inflammatory stress. We would first like to assess whether there are differences between the inflammatory response in tendinopathic and healthy TDSCs. We would then investigate whether a high glucose level may lead to changes in the inflammatory response in healthy tendon cells.MethodsTendinopathic TDSCs were cultured from 2 torn rotator cuff tendons and 1 ruptured patellar tendon. Healthy TDSCs were cultured from 3 gender matched healthy hamstring tendons. Cells were stimulated by either 2ng/ml IL-1B for 24 hours, 11.1 mmol/L glucose for 24 hours, or both. mRNA was collected and processed for qPCR targeting B-actin, ALOX12, ALOX15, FPR1, FPR2, ChemR23, and COX2.ResultsUpregulation of FPR1 (p=0.050) ChemR23 (p=0.050), ALOX15 (p=0.050) was significantly weakened when comparing tendinopathic and healthy TDSCs stimulated with IL-1b. The upregulation of ALOX15 (p=0.050), was significantly lower in stimulated healthy TDSCs in a high glucose environment when comparing with those stimulated under a regular glucose level. A high glucose level also induced upregulation of COX2 (p=0.046) in healthy TDSCs and tendinopathic TDSCs (p=0.050).ConclusionThe results of this study provide a possible explanation to the increased risk to develop tendinopathy in diabetic patients. Chronic inflammation observed in tendinopathy may be due to the weakening of pro-resolving responses in tendinopathic TDSCs, and a high glucose environment may lead to chronic inflammation and ultimately tendinopathy by persistent stimulation and weakening of pro-resolving response in healthy TDSCs.

Understanding cellular and molecular mechanisms of pathogenesis of diabetic tendinopathy

“…There is accumulating evidence that inflammatory cells are present, and chronic inflammation is a feature of tendinopathy[ 85 , 86 ], especially diabetic tendinopathy[ 3 ]. Kwan et al [ 87 ] showed that the mRNA expression of COX2 was increased in both healthy and tendinopathic TSPCs under high glucose conditions, while the upregulation of FPR1, ChemR23, and ALOX15 mRNA was significantly weakened in tendinopathic TSPCs upon IL-1β stimulation compared with that of healthy TSPCs, and the upregulation of ALOX15 mRNA was also weakened in IL-1β stimulated healthy TSPCs after preincubation in a high glucose environment. These results suggest that high glucose conditions may stimulate inflammation in tendinopathy and weaken the ability of pro-resolving response in TSPCs.…”

“…These results not only reveal the pathological mechanisms of diabetic tendinopathy but also provide a new potential treatment strategy. Kwan et al [ 87 ] showed that high glucose conditions stimulated an inflammatory response and increased COX2 in both healthy and tendinopathic TSPCs; high glucose also weakened the pro-resolving responses, with decreased expression of FPR1, ChemR23, and ALOX15 in tendinopathic TSPCs and ALOX15 in healthy TSPCs, which may cause persistent chronic inflammation in tendinopathic tendons and increase the risk of diabetic tendinopathy. The potential mechanisms associated with TSPCs during the progression of diabetic tendinopathy are summarized in Figure 2 .…”

Inflammatory mechanisms linking obesity and tendinopathy

“…In this context, hyperglycemia was reported to increase ROS production and mRNA expression of NADPH oxidase 1 and 4, IL-6, MMP-2, MMP-9, MM-13, TIMP-1 and TIMP-2 in tendon cells [ 107 , 108 ]. Besides, a high glucose concentration was also reported to upregulate the mRNA expression of COX-2 in healthy TDSCs and tendinopathic TDSCs [ 109 ]. The expression of ALOX15 was significantly reduced in IL-1β stimulated healthy TDSCs at a high glucose level, suggesting that the inflammation pro-resolving response of TDSCs was weakened in a high glucose environment [ 109 ].…”

The impact of type 2 diabetes on the development of tendinopathy

“…In another study from Kwan and colleagues, TDSCs were isolated from tendinopathic and healthy human specimens and exposed to IL‐1β, high glucose or both. High glucose increased cyclooxygenase‐2 levels in both groups, while tendinopathic TDSCs showed a reduced expression of arachidonate lipoxygenase‐15, formyl peptide receptor‐1 and chemerin receptor‐23, which are all involved in the production of specialized pro‐resolving mediators, thus stimulating a pro‐inflammatory response 45 …”