title: Compromised Neurotrophic and Angiogenic Regenerative Capability during Tendon Healing in a Rat Model of Type-II Diabetes.
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.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
authors.forename: Aisha S
authors.initials: AS
authors.lastname: Ahmed
authors.affiliation: Karolinska Institutet, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Karolinska Institutet, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Alim M D
authors.initials: AM
authors.lastname: Abdul
authors.affiliation: Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Center for Family and Community Medicine (CeFAM), Huddinge, Sweden.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Karolinska Institutet, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Claes-Göran
authors.initials: CG
authors.lastname: Östenson
authors.affiliation: McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, AB, Canada.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Salo
authors.affiliation: McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, AB, Canada.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Hewitt
authors.affiliation: McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, AB, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Hart
authors.affiliation: Karolinska Institutet, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Ackermann
mesh_terms: D000125:Achilles Tendon / Q000293:injuries* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D015870:Gene Expression; D008297:Male; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism; D013373:Substance P / Q000235:genetics / Q000378:metabolism; D013708:Tendon Injuries / Q000378:metabolism / Q000503:physiopathology*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018040:Receptors, Neurokinin-1; D013373:Substance P; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020813:Receptor, trkB