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

Date Published: July 7, 2017

Publisher: Public Library of Science

Author(s): Jessica E. Ackerman, Michael B. Geary, Caitlin A. Orner, Fatima Bawany, Alayna E. Loiselle, Chunfeng Zhao.

http://doi.org/10.1371/journal.pone.0181127

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.

Partial Text

The dramatic increase in type II diabetes mellitus (T2DM) as part of the obesity epidemic [1], is one of the most critical health challenges facing the U.S.; in 2012 more than 29 million people, or nearly 10% of the US population were diabetic, resulting in a health care burden of $254 billion [2]. T2DM results in systemic inflammation and is characterized by metabolic dysfunction including elevated plasma glucose levels (hyperglycemia). Among a plethora of systemic complications and co-morbidities arising from T2DM, the impact on the musculoskeletal system is emerging as an important disease manifestation. T2DM dramatically alters tendon homeostasis; diabetic tendons are generally fibrotic and display increased disorganization of the extracellular matrix (ECM) [3], although there is some variability in the degree to which different tendons are affected by T2DM [4, 5].

Type II diabetes alters baseline tendon function and impairs the normal tendon healing process. Clinically, diabetic tendons have decreased ROM and are more likely to re-tear or rupture following repair [24], suggesting that T2DM alters tissue organization and quality. Animal models have demonstrated decreased mechanical properties [7], and decreased collagen fiber organization [8] in diabetic tendons relative to non-diabetic controls. However, little is understood about the mechanisms that govern impaired healing in type II diabetics, as such there is currently no therapeutic approach to improve outcomes in these patients. In the present study we have demonstrated that repaired FTs of obese/ diabetic mice heal with prolonged scar formation, compromised mechanical properties, and increased deposition of extracellular matrix. Furthermore, elevated expression of markers associated with both the pro-inflammatory M1 macrophage phenotype, and the matrix deposition/ remodeling M2 macrophage are observed in obese/ diabetic repairs suggesting that an altered macrophage response may be associated with impairments in tendon healing that occur in type II diabetics.

 

Source:

http://doi.org/10.1371/journal.pone.0181127

 

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