Obesity/Type II diabetes alters macrophage polarization resulting in a fibrotic tendon healing response

Abstract

Type II Diabetes (T2DM) dramatically impairs the tendon healing response, resulting in decreased collagen organization and mechanics relative to non-diabetic tendons. Despite this burden, there remains a paucity of information regarding the mechanisms that govern impaired healing of diabetic tendons. Mice were placed on either a high fat diet (T2DM) or low fat diet (lean) and underwent flexor tendon transection and repair surgery. Healing was assessed via mechanical testing, histology and changes in gene expression associated with collagen synthesis, matrix remodeling, and macrophage polarization. Obese/diabetic tendons healed with increased scar formation and impaired mechanical properties. Consistent with this, prolonged and excess expression of extracellular matrix (ECM) components were observed in obese/T2DM tendons. Macrophages are involved in both inflammatory and matrix deposition processes during healing. Obese/T2DM tendons healed with increased expression of markers of pro-inflammatory M1 macrophages, and elevated and prolonged expression of M2 macrophages markers that are involved in ECM deposition. Here we demonstrate that tendons from obese/diabetic mice heal with increased scar formation and increased M2 polarization, identifying excess M2 macrophage activity and matrix synthesis as a potential mechanism of the fibrotic healing phenotype observed in T2DM tendons, and as such a potential target to improve tendon healing in T2DM.

Effects of Type II Diabetes Mellitus on Tendon Homeostasis and Healing

“…Despite the well‐known complications that arise during diabetic tendon healing, there are few animal studies that examine the mechanisms and cell types involved in the abnormal healing response (Table ). Similar to what is seen in clinical cases of T2DM tendon injury, T2DM rodent models exhibit impaired tendon healing . More specifically, using the DIO mouse model, David et al reported increased extracellular matrix disorganization, limited tenocyte migration, and impaired biomechanical properties following a biopsy punch injury to the FDL mid‐substance.…”

“…More specifically, using the DIO mouse model, David et al reported increased extracellular matrix disorganization, limited tenocyte migration, and impaired biomechanical properties following a biopsy punch injury to the FDL mid‐substance. We recently reported that FDL tendons from DIO T2DM mice heal with an amplified fibrotic response characterized by increased expression of Col1 , collagen type 3 ( Col3 ), Mmp9 , and Mmp2 , impaired range of motion, and increased gliding resistance following transection and repair, compared with mice fed a low‐fat diet . Importantly, we also observed alterations in macrophage polarization including increased and prolonged markers of M2 macrophage activity, suggesting that aberrant activity of these cells may be critically involved in fibrotic T2DM tendon healing.…”

“…As with human cases, the majority of diabetic mouse models are obese with varying levels of severity. Male C57BL/6J mice are commonly used to model diet‐induced obesity (DIO) and associated T2DM as they become obese and develop decreased glucose tolerance with moderate insulin resistance when fed a high‐fat diet (HFD) . The DIO mouse model also recapitulates hallmark complications of human T2DM including impaired wound healing and peripheral neuropathy .…”

Disruption of Monocyte and Macrophage Homeostasis in Periodontitis

“…Interestingly, we observed a higher abundance of M1 macrophage phenotype in healthy sites of patients with T2DM compared to healthy sites in non-diabetes patients. Macrophage-mediated regulation of chronic inflammation and especially M1 polarization plays a key role in the pathogenesis of diabetic complications (32,33), and may explain the higher susceptibility of these individuals to periodontitis. These findings were corroborated by the ex vivo blood monocyte data indicating transcriptional changes in circulating blood monocytes of patients with T2DM versus non-diabetes individuals even before the cells reside in the gingival tissue.…”

Non-invasive ultrasound quantification of Scar Tissue Volume predicts functional changes during tendon healing

“…Only female C57Bl/6J mice were used, while male and female S100a4 GFP/+ and WT used in equal proportions across genotypes. At 10-12 weeks of age, mice underwent surgical transection and repair of the flexor digitorum longus (FDL) tendon in the hind paw as we have previously described 4,10-14 . Briefly, the distal FDL tendon was exposed and transected; two horizontal 8-0 sutures were placed in the intact tendon ends and the tendon was sutured to approximate an end-to-end repair.…”