Abstract
Metabolic diseases such as diabetes mellitus type-II (DM-II) may increase the risk of suffering painful connective tissue disorders and tendon ruptures. The pathomechanisms, however, by which diabetes adversely affects connective tissue matrix metabolism and regeneration, still need better definition. Our aim was to study the effect of DM-II on expressional changes of neuro- and angiotrophic mediators and receptors in intact and healing Achilles tendon. The right Achilles tendon was transected in 5 male DM-II Goto-Kakizaki (GK) and 4 age-matched Wistar control rats. The left Achilles tendons were left intact. At week 2 post-injury, NGF, BDNF, TSP, and receptors TrkA, TrkB and Nk1 gene expression was studied by quantitative RT-PCR (qRT-PCR) and their protein distribution by immunohistochemistry in intact and injured tendons. The expression of tendon-related markers, Scleraxis (SCX) and Tenomodulin (TNMD), was evaluated by qRT-PCR in intact and injured tendons. Injured tendons of diabetic GK rats exhibited significantly down-regulated Ngf and Tsp1 mRNA and corresponding protein levels, and down-regulated Trka gene expression compared to injured Wistar controls. Intact tendons of DM-II GK rats displayed reduced mRNA levels for Ngf, Tsp1 and Trkb compared to corresponding intact non-diabetic tendons. Up-regulated Scx and Tnmd gene expression was observed in injured tendons of normal and diabetic GK rats compared to intact Wistar controls. However, these molecules were not up-regulated in injured DM-II GK rats compared to their corresponding controls. Our results suggest that DM-II has detrimental effects on neuro- and angiotrophic pathways, and such effects may reflect the compromised repair seen in diabetic Achilles tendon. Thus, novel approaches for regeneration of injured, including tendinopathic, and surgically repaired diabetic tendons may include therapeutic molecular modulation of neurotrophic pathways such as NGF and its receptors.
Highlights
Patients with metabolic disorders such as type-2 diabetes mellitus (DM) are at increased risk of suffering various musculoskeletal disorders [1,2]
The presence of diabetes in GK rats was confirmed by fasting blood glucose levels, which were significantly higher in diabetic GK rats compared to Wistar controls, as reported previously [19]
This study demonstrates a compromised expression of neuro- and angiotrophic ligands (NGF, brain-derived neurotrophic factor (BDNF), TSP1), as well as receptor (TrkA, TrkB, neurokinin 1 (NK1)) genes and proteins in an animal model of type-II DM, findings which likely are contributing factors in altered healing in the diabetic state
Summary
Patients with metabolic disorders such as type-2 diabetes mellitus (DM) are at increased risk of suffering various musculoskeletal disorders [1,2]. Painful connective tissue diseases associated with DM, such as osteoarthritis, capsulitis, tendinopathy and tendon ruptures can result in considerable disability due to compromised regenerative capability. The underlying neurotrophic and angiotrophic pathways, which are altered in connective tissue homeostasis and regeneration of metabolic diseases, are far from completely understood [3,4,5]. Connective tissues are comprised of cells (mainly fibroblasts) and a tissue-specialized extracellular matrix (ECM) containing proteoglycans, polysaccharides, and collagen. The homeostasis and regenerative capability of the ECM is vital for mechanical integrity, tissue growth and wound healing. Patients with diabetes often exhibit delayed and/or defective tissue healing, associated with impaired formation of a collagen matrix, compromised angiogenesis and hampered neuronal function [4, 7]
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